265 results on '"Grossman LI"'
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2. Foreword to conference‐workshop on advanced education in endodontics
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Grossman, LI, primary
- Published
- 1969
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3. Epstein-Barr virus induces adhesion molecule CD226 (DNAM-1) expression during primary B cell transformation into lymphoblastoid cell lines
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Grossman Lisa V, Nikitin Pavel A, Dave Sandeep, Tourigny Jason P, and Luftig Micah A
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 ,Infectious and parasitic diseases ,RC109-216 - Published
- 2012
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4. A mitochondrial regulator protein, MNRR1, is elevated in the maternal blood of women with preeclampsia.
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Suksai M, Romero R, Bosco M, Gotsch F, Jung E, Chaemsaithong P, Tarca AL, Gudicha DW, Gomez-Lopez N, Arenas-Hernandez M, Meyyazhagan A, Grossman LI, Aras S, and Chaiworapongsa T
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- Female, Humans, Pregnancy, Case-Control Studies, Hypoxia, Mitochondrial Proteins, Placenta metabolism, Reactive Oxygen Species metabolism, Retrospective Studies, Mitochondrial Diseases metabolism, Mitochondrial Diseases pathology, Pre-Eclampsia
- Abstract
Objective: Preeclampsia, one of the most serious obstetric complications, is a heterogenous disorder resulting from different pathologic processes. However, placental oxidative stress and an anti-angiogenic state play a crucial role. Mitochondria are a major source of cellular reactive oxygen species. Abnormalities in mitochondrial structures, proteins, and functions have been observed in the placentae of patients with preeclampsia, thus mitochondrial dysfunction has been implicated in the mechanism of the disease. Mitochondrial nuclear retrograde regulator 1 (MNRR1) is a newly characterized bi-organellar protein with pleiotropic functions. In the mitochondria, this protein regulates cytochrome c oxidase activity and reactive oxygen species production, whereas in the nucleus, it regulates the transcription of a number of genes including response to tissue hypoxia and inflammatory signals. Since MNRR1 expression changes in response to hypoxia and to an inflammatory signal, MNRR1 could be a part of mitochondrial dysfunction and involved in the pathologic process of preeclampsia. This study aimed to determine whether the plasma MNRR1 concentration of women with preeclampsia differed from that of normal pregnant women., Methods: This retrospective case-control study included 97 women with preeclampsia, stratified by gestational age at delivery into early (<34 weeks, n = 40) and late (≥34 weeks, n = 57) preeclampsia and by the presence or absence of placental lesions consistent with maternal vascular malperfusion (MVM), the histologic counterpart of an anti-angiogenic state. Women with an uncomplicated pregnancy at various gestational ages who delivered at term served as controls ( n = 80) and were further stratified into early ( n = 25) and late ( n = 55) controls according to gestational age at venipuncture. Maternal plasma MNRR1 concentrations were determined by an enzyme-linked immunosorbent assay., Results: 1) Women with preeclampsia at the time of diagnosis (either early or late disease) had a significantly higher median (interquartile range, IQR) plasma MNRR1 concentration than the controls [early preeclampsia: 1632 (924-2926) pg/mL vs. 630 (448-4002) pg/mL, p = .026, and late preeclampsia: 1833 (1441-5534) pg/mL vs. 910 (526-6178) pg/mL, p = .021]. Among women with early preeclampsia, those with MVM lesions in the placenta had the highest median (IQR) plasma MNRR1 concentration among the three groups [with MVM: 2066 (1070-3188) pg/mL vs. without MVM: 888 (812-1781) pg/mL, p = .03; and with MVM vs. control: 630 (448-4002) pg/mL, p = .04]. There was no significant difference in the median plasma MNRR1 concentration between women with early preeclampsia without MVM lesions and those with an uncomplicated pregnancy ( p = .3). By contrast, women with late preeclampsia, regardless of MVM lesions, had a significantly higher median (IQR) plasma MNRR1 concentration than women in the control group [with MVM: 1609 (1392-3135) pg/mL vs. control: 910 (526-6178), p = .045; and without MVM: 2023 (1578-8936) pg/mL vs. control, p = .01]., Conclusions: MNRR1, a mitochondrial regulator protein, is elevated in the maternal plasma of women with preeclampsia (both early and late) at the time of diagnosis. These findings may reflect some degree of mitochondrial dysfunction, intravascular inflammation, or other unknown pathologic processes that characterize this obstetrical syndrome.
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- 2024
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5. Resonance Raman spectral analysis of the heme site structure of cytochrome c oxidase with its positive regulator CHCHD2.
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Yanagisawa S, Kamei T, Shimada A, Gladyck S, Aras S, Hüttemann M, Grossman LI, and Kubo M
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- Humans, Protein Binding, Spectrum Analysis, Raman methods, Electron Transport Complex IV chemistry, Electron Transport Complex IV metabolism, Heme chemistry, Heme metabolism, DNA-Binding Proteins chemistry, DNA-Binding Proteins metabolism, Mitochondrial Proteins chemistry, Mitochondrial Proteins metabolism, Transcription Factors metabolism, Transcription Factors chemistry
- Abstract
Cytochrome c oxidase (CcO) reduces O
2 , pumps protons in the mitochondrial respiratory chain, and is essential for oxygen consumption in the cell. The coiled-coil-helix-coiled-coil-helix domain-containing 2 (CHCHD2; also known as mitochondrial nuclear retrograde regulator 1 [MNRR1], Parkinson's disease 22 [PARK22] and aging-associated gene 10 protein [AAG10]) is a protein that binds to CcO from the intermembrane space and positively regulates the activity of CcO. Despite the importance of CHCHD2 in mitochondrial function, the mechanism of action of CHCHD2 and structural information regarding its binding to CcO remain unknown. Here, we utilized visible resonance Raman spectroscopy to investigate the structural changes around the hemes in CcO in the reduced and CO-bound states upon CHCHD2 binding. We found that CHCHD2 has a significant impact on the structure of CcO in the reduced state. Mapping of the heme peripheries that result in Raman spectral changes in the structure of CcO highlighted helices IX and X near the hemes as sites where CHCHD2 takes action. Part of helix IX is exposed in the intermembrane space, whereas helix X, located between both hemes, may play a key role in proton uptake to a proton-loading site in the reduced state for proton pumping. Taken together, our results suggested that CHCHD2 binds near helix IX and induces a structural change in helix X, accelerating proton uptake., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)- Published
- 2024
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6. Mitochondrial Oxidative Phosphorylation in Viral Infections.
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Purandare N, Ghosalkar E, Grossman LI, and Aras S
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- Humans, Mitochondria metabolism, Apoptosis physiology, Signal Transduction, Phosphorylation, Oxidative Stress, Oxidative Phosphorylation, Virus Diseases metabolism
- Abstract
Mitochondria have been identified as the "powerhouse" of the cell, generating the cellular energy, ATP, for almost seven decades. Research over time has uncovered a multifaceted role of the mitochondrion in processes such as cellular stress signaling, generating precursor molecules, immune response, and apoptosis to name a few. Dysfunctional mitochondria resulting from a departure in homeostasis results in cellular degeneration. Viruses hijack host cell machinery to facilitate their own replication in the absence of a bonafide replication machinery. Replication being an energy intensive process necessitates regulation of the host cell oxidative phosphorylation occurring at the electron transport chain in the mitochondria to generate energy. Mitochondria, therefore, can be an attractive therapeutic target by limiting energy for viral replication. In this review we focus on the physiology of oxidative phosphorylation and on the limited studies highlighting the regulatory effects viruses induce on the electron transport chain.
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- 2023
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7. Evidence for the participation of CHCHD2/MNRR1, a mitochondrial protein, in spontaneous labor at term and in preterm labor with intra-amniotic infection.
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Bosco M, Romero R, Gallo DM, Suksai M, Gotsch F, Jung E, Chaemsaithong P, Tarca AL, Gomez-Lopez N, Arenas-Hernandez M, Meyyazhagan A, Al Qasem M, Franchi MP, Grossman LI, Aras S, and Chaiworapongsa T
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- Infant, Newborn, Pregnancy, Female, Humans, Interleukin-6 analysis, Cross-Sectional Studies, Mitochondrial Proteins, Inflammation metabolism, Amniotic Fluid metabolism, Gestational Age, DNA-Binding Proteins analysis, DNA-Binding Proteins metabolism, Transcription Factors analysis, Transcription Factors metabolism, Chorioamnionitis metabolism, Obstetric Labor, Premature metabolism, Sepsis, Fetal Membranes, Premature Rupture metabolism
- Abstract
Objective: Intra-amniotic inflammation (IAI), associated with either microbe (infection) or danger signals (sterile), plays a major role in the pathophysiology of preterm labor and delivery. Coiled-Coil-Helix-Coiled-Coil-Helix Domain Containing 2 (CHCHD2) [also known as Mitochondrial Nuclear Retrograde Regulator 1 (MNRR1)], a mitochondrial protein involved in oxidative phosphorylation and cell survival, is capable of sensing tissue hypoxia and inflammatory signaling. The ability to maintain an appropriate energy balance at the cellular level while adapting to environmental stress is essential for the survival of an organism. Mitochondrial dysfunction has been observed in acute systemic inflammatory conditions, such as sepsis, and is proposed to be involved in sepsis-induced multi-organ failure. The purpose of this study was to determine the amniotic fluid concentrations of CHCHD2/MNRR1 in pregnant women, women at term in labor, and those in preterm labor (PTL) with and without IAI., Methods: This cross-sectional study comprised patients allocated to the following groups: (1) mid-trimester ( n = 16); (2) term in labor ( n = 37); (3) term not in labor ( n = 22); (4) PTL without IAI who delivered at term ( n = 25); (5) PTL without IAI who delivered preterm ( n = 47); and (6) PTL with IAI who delivered preterm ( n = 53). Diagnosis of IAI (amniotic fluid interleukin-6 concentration ≥2.6 ng/mL) included cases associated with microbial invasion of the amniotic cavity and those of sterile nature (absence of detectable bacteria, using culture and molecular microbiology techniques). Amniotic fluid and maternal plasma CHCHD2/MNRR1 concentrations were determined with a validated and sensitive immunoassay., Results: (1) CHCHD2/MNRR1 was detectable in all amniotic fluid samples and women at term without labor had a higher amniotic fluid CHCHD2/MNRR1 concentration than those in the mid-trimester ( p = 0.003); (2) the amniotic fluid concentration of CHCHD2/MNRR1 in women at term in labor was higher than that in women at term without labor ( p = 0.01); (3) women with PTL and IAI had a higher amniotic fluid CHCHD2/MNRR1 concentration than those without IAI, either with preterm ( p < 0.001) or term delivery ( p = 0.01); (4) women with microbial-associated IAI had a higher amniotic fluid CHCHD2/MNRR1 concentration than those with sterile IAI ( p < 0.001); (5) among women with PTL and IAI, the amniotic fluid concentration of CHCHD2/MNRR1 correlated with that of interleukin-6 (Spearman's Rho = 0.7; p < 0.001); and (6) no correlation was observed between amniotic fluid and maternal plasma CHCHD2/MNRR1 concentrations among women with PTL., Conclusion: CHCHD2/MNRR1 is a physiological constituent of human amniotic fluid in normal pregnancy, and the amniotic concentration of this mitochondrial protein increases during pregnancy, labor at term, and preterm labor with intra-amniotic infection. Hence, CHCHD2/MNRR1 may be released into the amniotic cavity by dysfunctional mitochondria during microbial-associated IAI.
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- 2023
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8. Clinical chorioamnionitis at term is characterized by changes in the plasma concentration of CHCHD2/MNRR1, a mitochondrial protein.
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Bosco M, Romero R, Gallo DM, Suksai M, Gotsch F, Jung E, Chaemsaithong P, Tarca AL, Gomez-Lopez N, Arenas-Hernandez M, Meyyazhagan A, Al Qasem M, Franchi MP, Grossman LI, Aras S, and Chaiworapongsa T
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- Pregnancy, Female, Humans, Animals, Mice, Mitochondrial Proteins, Cross-Sectional Studies, Inflammation, Amniotic Fluid metabolism, DNA-Binding Proteins analysis, Transcription Factors analysis, Transcription Factors metabolism, Chorioamnionitis metabolism, Labor, Obstetric metabolism
- Abstract
Objective: Mitochondrial dysfunction was observed in acute systemic inflammatory conditions such as sepsis and might be involved in sepsis-induced multi-organ failure. Coiled-Coil-Helix-Coiled-Coil-Helix Domain Containing 2 (CHCHD2), also known as Mitochondrial Nuclear Retrograde Regulator 1 (MNRR1), a bi-organellar protein located in the mitochondria and the nucleus, is implicated in cell respiration, survival, and response to tissue hypoxia. Recently, the reduction of the cellular CHCHD2/MNRR1 protein, as part of mitochondrial dysfunction, has been shown to play a role in the amplification of inflammatory cytokines in a murine model of lipopolysaccharide-induced systemic inflammation. The aim of this study was to determine whether the plasma concentration of CHCHD2/MNRR1 changed during human normal pregnancy, spontaneous labor at term, and clinical chorioamnionitis at term., Methods: We conducted a cross-sectional study that included the following groups: 1) non-pregnant women ( n = 17); 2) normal pregnant women at various gestational ages from the first trimester until term ( n = 110); 3) women at term with spontaneous labor ( n = 50); and 4) women with clinical chorioamnionitis at term in labor ( n = 25). Plasma concentrations of CHCHD2/MNRR1 were assessed by an enzyme-linked immunosorbent assay., Results: 1) Pregnant women at term in labor with clinical chorioamnionitis had a significantly higher plasma CHCHD2/MNRR1 concentration than those in labor without chorioamnionitis ( p = .003); 2) CHCHD2/MNRR1 is present in the plasma of healthy non-pregnant and normal pregnant women without significant differences in its plasma concentrations between the two groups; 3) there was no correlation between maternal plasma CHCHD2/MNRR1 concentration and gestational age at venipuncture; and 4) plasma CHCHD2/MNRR1 concentration was not significantly different in women at term in spontaneous labor compared to those not in labor., Conclusions: CHCHD2/MNRR1 is physiologically present in the plasma of healthy non-pregnant and normal pregnant women, and its concentration does not change with gestational age and parturition at term. However, plasma CHCHD2/MNRR1 is elevated in women at term with clinical chorioamnionitis. CHCHD2/MNRR1, a novel bi-organellar protein located in the mitochondria and the nucleus, is released into maternal plasma during systemic inflammation.
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- 2023
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9. The MNRR1 activator nitazoxanide abrogates lipopolysaccharide-induced preterm birth in mice.
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Purandare N, Gomez-Lopez N, Arenas-Hernandez M, Galaz J, Romero R, Xi Y, Fribley AM, Grossman LI, and Aras S
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- Infant, Newborn, Female, Humans, Animals, Mice, Lipopolysaccharides, Nitro Compounds adverse effects, Inflammation chemically induced, Amniotic Fluid, DNA-Binding Proteins, Transcription Factors genetics, Premature Birth prevention & control, Chorioamnionitis
- Abstract
Intra-amniotic inflammation leading to preterm birth is one of the leading causes of neonatal morbidity and mortality. We recently reported that the mitochondrial levels of MNRR1 (Mitochondrial Nuclear Retrograde, Regulator 1; also called CHCHD2, AAG10, or PARK22), an important bi-organellar regulator of cellular function, are reduced in the context of inflammation and that genetic and pharmacological increases in MNRR1 levels can counter the inflammatory profile. Herein, we show that nitazoxanide, a clinically approved drug, is an activator of MNRR1 and abrogates preterm birth in a well-characterized murine model caused by intra-amniotic lipopolysaccharide (LPS) injection., Competing Interests: Declaration of competing interest The authors state that they have no conflicts to declare., (Copyright © 2023 Elsevier Ltd. All rights reserved.)
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- 2023
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10. Non-coding regions of nuclear-DNA-encoded mitochondrial genes and intergenic sequences are targeted by autoantibodies in breast cancer.
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Obaidat D, Giordo R, Kleinbrink EL, Banisad E, Grossman LI, Arshad R, Stark A, Maroun MC, Lipovich L, and Fernandez-Madrid F
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Autoantibodies against mitochondrial-derived antigens play a key role in chronic tissue inflammation in autoimmune disorders and cancers. Here, we identify autoreactive nuclear genomic DNA (nDNA)-encoded mitochondrial gene products ( GAPDH, PKM2, GSTP1, SPATA5, MFF, TSPOAP1, PHB2, COA4, and HAGH ) recognized by breast cancer (BC) patients' sera as nonself, supporting a direct relationship of mitochondrial autoimmunity to breast carcinogenesis. Autoreactivity of multiple nDNA-encoded mitochondrial gene products was mapped to protein-coding regions, 3' untranslated regions (UTRs), as well as introns. In addition, autoantibodies in BC sera targeted intergenic sequences that may be parts of long non-coding RNA (lncRNA) genes, including LINC02381 and other putative lncRNA neighbors of the protein-coding genes ERCC4, CXCL13, SOX3, PCDH1, EDDM3B, and GRB2 . Increasing evidence indicates that lncRNAs play a key role in carcinogenesis. Consistent with this, our findings suggest that lncRNAs, as well as mRNAs of nDNA-encoded mitochondrial genes, mechanistically contribute to BC progression. This work supports a new paradigm of breast carcinogenesis based on a globally dysfunctional genome with altered function of multiple mitochondrial and non-mitochondrial oncogenic pathways caused by the effects of autoreactivity-induced dysregulation of multiple genes and their products. This autoimmunity-based model of carcinogenesis will open novel avenues for BC treatment., Competing Interests: Author LL has been collaborating with the Shenzhen Huayuan Biological Science Research Institute since 2019. This academic-industry research collaboration does not entail any past or present appointments at or compensation by the company, does not entail consulting, and is not remunerated. The research reported in this paper is completely outside the scope of this collaboration. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Obaidat, Giordo, Kleinbrink, Banisad, Grossman, Arshad, Stark, Maroun, Lipovich and Fernandez-Madrid.)
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- 2023
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11. MNRR1 is a driver of ovarian cancer progression.
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Chehade H, Purandare N, Fox A, Adzibolosu N, Jayee S, Singh A, Tedja R, Gogoi R, Aras S, Grossman LI, Mor G, and Alvero AB
- Abstract
Cancer progression requires the acquisition of mechanisms that support proliferative potential and metastatic capacity. MNRR1 (also CHCHD2, PARK22, AAG10) is a bi-organellar protein that in the mitochondria can bind to Bcl-xL to enhance its anti-apoptotic function, or to respiratory chain complex IV (COX IV) to increase mitochondrial respiration. In the nucleus, it can act as a transcription factor and promote the expression of genes involved in mitochondrial biogenesis, migration, and cellular stress response. Given that MNRR1 can regulate both apoptosis and mitochondrial respiration, as well as migration, we hypothesize that it can modulate metastatic spread. Using ovarian cancer models, we show heterogeneous protein expression levels of MNRR1 across samples tested and cell-dependent control of its stability and binding partners. In addition to its anti-apoptotic and bioenergetic functions, MNRR1 is both necessary and sufficient for a focal adhesion and ECM repertoire that can support spheroid formation. Its ectopic expression is sufficient to induce the adhesive glycoprotein THBS4 and the type 1 collagen, COL1A1. Conversely, its deletion leads to significant downregulation of these genes. Furthermore, loss of MNRR1 leads to delay in tumor growth, curtailed carcinomatosis, and improved survival in a syngeneic ovarian cancer mouse model. These results suggest targeting MNRR1 may improve survival in ovarian cancer patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)
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- 2023
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12. Mitochondrial oxygen sensing of acute hypoxia in specialized cells - Is there a unifying mechanism?
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Pak O, Nolte A, Knoepp F, Giordano L, Pecina P, Hüttemann M, Grossman LI, Weissmann N, and Sommer N
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- Humans, Hypoxia, Protein Isoforms, Reactive Oxygen Species metabolism, Electron Transport Complex IV metabolism, Oxygen metabolism
- Abstract
Acclimation to acute hypoxia through cardiorespiratory responses is mediated by specialized cells in the carotid body and pulmonary vasculature to optimize systemic arterial oxygenation and thus oxygen supply to the tissues. Acute oxygen sensing by these cells triggers hyperventilation and hypoxic pulmonary vasoconstriction which limits pulmonary blood flow through areas of low alveolar oxygen content. Oxygen sensing of acute hypoxia by specialized cells thus is a fundamental pre-requisite for aerobic life and maintains systemic oxygen supply. However, the primary oxygen sensing mechanism and the question of a common mechanism in different specialized oxygen sensing cells remains unresolved. Recent studies unraveled basic oxygen sensing mechanisms involving the mitochondrial cytochrome c oxidase subunit 4 isoform 2 that is essential for the hypoxia-induced release of mitochondrial reactive oxygen species and subsequent acute hypoxic responses in both, the carotid body and pulmonary vasculature. This review compares basic mitochondrial oxygen sensing mechanisms in the pulmonary vasculature and the carotid body., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)
- Published
- 2022
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13. Lipopolysaccharide induces placental mitochondrial dysfunction in murine and human systems by reducing MNRR1 levels via a TLR4-independent pathway.
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Purandare N, Kunji Y, Xi Y, Romero R, Gomez-Lopez N, Fribley A, Grossman LI, and Aras S
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Mitochondria play a key role in placental growth and development, and mitochondrial dysfunction is associated with inflammation in pregnancy pathologies. However, the mechanisms whereby placental mitochondria sense inflammatory signals are unknown. Mitochondrial nuclear retrograde regulator 1 (MNRR1) is a bi-organellar protein responsible for mitochondrial function, including optimal induction of cellular stress-responsive signaling pathways. Here, in a lipopolysaccharide-induced model of systemic placental inflammation, we show that MNRR1 levels are reduced both in mouse placental tissues in vivo and in human trophoblastic cell lines in vitro . MNRR1 reduction is associated with mitochondrial dysfunction, enhanced oxidative stress, and activation of pro-inflammatory signaling. Mechanistically, we uncover a non-conventional pathway independent of Toll-like receptor 4 (TLR4) that results in ATM kinase-dependent threonine phosphorylation that stabilizes mitochondrial protease YME1L1, which targets MNRR1. Enhancing MNRR1 levels abrogates the bioenergetic defect and induces an anti-inflammatory phenotype. We therefore propose MNRR1 as an anti-inflammatory therapeutic in placental inflammation., Competing Interests: The authors declare that they have no competing interests., (© 2022 The Authors.)
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- 2022
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14. An explanation for the decreased severity of liver malfunction in Niemann-Pick C1 disease with age.
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Erickson RP, Grossman LI, and Aras S
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- Animals, Disease Models, Animal, Humans, Mice, Liver, Niemann-Pick Disease, Type C genetics
- Abstract
Niemann-Pick C disease frequently presents as severe cholestatic disease in infants. However, it progressively becomes less of a problem as children age. We have found that, in an appropriate mouse model, liver cholesterol levels, which are initially very high, decrease while mitochondrial function, initially quite compromised, increases with age. The key mitochondrial regulator, MNRR1, increases in parallel with the increase in mitochondrial function. These changes appear to explain the amelioration of the liver disease that occurs with time in this disorder., (© 2022. The Author(s), under exclusive licence to Institute of Plant Genetics Polish Academy of Sciences.)
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- 2022
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15. Fetal and maternal NLRP3 signaling is required for preterm labor and birth.
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Motomura K, Romero R, Galaz J, Tao L, Garcia-Flores V, Xu Y, Done B, Arenas-Hernandez M, Miller D, Gutierrez-Contreras P, Farias-Jofre M, Aras S, Grossman LI, Tarca AL, and Gomez-Lopez N
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- Animals, Female, Fetus metabolism, Humans, Infant, Newborn, Inflammation, Mice, Pregnancy, NLR Family, Pyrin Domain-Containing 3 Protein genetics, NLR Family, Pyrin Domain-Containing 3 Protein metabolism, Obstetric Labor, Premature genetics, Obstetric Labor, Premature metabolism, Premature Birth etiology, Premature Birth genetics, Premature Birth metabolism
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Preterm birth is the leading cause of neonatal morbidity and mortality worldwide. One of every 4 preterm neonates is born to a mother with intra-amniotic inflammation driven by invading bacteria. However, the molecular mechanisms underlying this hostile immune response remain unclear. Here, we used a translationally relevant model of preterm birth in Nlrp3-deficient and -sufficient pregnant mice to identify what we believe is a previously unknown dual role for the NLRP3 pathway in the fetal and maternal signaling required for the premature onset of the labor cascade leading to fetal injury and neonatal death. Specifically, the NLRP3 sensor molecule and/or inflammasome is essential for triggering intra-amniotic and decidual inflammation, fetal membrane activation, uterine contractility, and cervical dilation. NLRP3 also regulates the functional status of neutrophils and macrophages in the uterus and decidua, without altering their influx, as well as maternal systemic inflammation. Finally, both embryo transfer experimentation and heterozygous mating systems provided mechanistic evidence showing that NLRP3 signaling in both the fetus and the mother is required for the premature activation of the labor cascade. These data provide insights into the mechanisms of fetal-maternal dialog in the syndrome of preterm labor and indicate that targeting the NLRP3 pathway could prevent adverse perinatal outcomes.
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- 2022
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16. Intraperitoneal Triamcinolone Reduces Postoperative Adhesions, Possibly through Alteration of Mitochondrial Function.
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Purandare N, Kramer KJ, Minchella P, Ottum S, Walker C, Rausch J, Chao CR, Grossman LI, Aras S, and Recanati MA
- Abstract
Adhesions frequently occur postoperatively, causing morbidity. In this noninterventional observational cohort study, we enrolled patients who presented for repeat abdominal surgery, after a history of previous abdominal myomectomy, from March 1998 to June 20210 at St. Vincent's Catholic Medical Centers. The primary outcome of this pilot study was to compare adhesion rates, extent, and severity in patients who were treated with intraperitoneal triamcinolone acetonide during the initial abdominal myomectomy ( n = 31) with those who did not receive any antiadhesion interventions ( n = 21), as documented on retrospective chart review. Adhesions were blindly scored using a standard scoring system. About 32% of patients were found to have adhesions in the triamcinolone group compared to 71% in the untreated group ( p < 0.01). Compared to controls, adhesions were significantly less in number (0.71 vs. 2.09, p < 0.005), severity (0.54 vs. 1.38, p < 0.004), and extent (0.45 vs. 1.28, p < 0.003). To understand the molecular mechanisms, human fibroblasts were incubated in hypoxic conditions and treated with triamcinolone or vehicle. In vitro studies showed that triamcinolone directly prevents the surge of reactive oxygen species triggered by 2% hypoxia and prevents the increase in TGF-β1 that leads to the irreversible conversion of fibroblasts to an adhesion phenotype. Triamcinolone prevents the increase in reactive oxygen species through alterations in mitochondrial function that are HIF-1α-independent. Controlling mitochondrial function may thus allow for adhesion-free surgery and reduced postoperative complications.
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- 2022
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17. Corrigendum to "Decreased membrane cholesterol in liver mitochondria of the point mutation mouse model of juvenile Niemann-Pick C1, Npc1 nmf164 " [Mitochondrion 51 (2019) 15-21].
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Erickson RP, Aras S, Purandare N, Hüttemann M, Liu J, Dragotto J, Fiorenza MT, and Grossman LI
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- 2021
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18. Mitochondrial respiration is controlled by Allostery, Subunit Composition and Phosphorylation Sites of Cytochrome c Oxidase: A trailblazer's tale - Bernhard Kadenbach.
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Vogt S, Ramzan R, Grossman LI, Singh KK, Ferguson-Miller S, Yoshikawa S, Lee I, and Hüttemann M
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- Animals, Electron Transport Complex IV genetics, Isoenzymes, Mitochondria genetics, Electron Transport Complex IV metabolism, Gene Expression Regulation, Enzymologic physiology, Mitochondria metabolism, Oxygen Consumption physiology
- Abstract
In memoriam of Bernhard Kadenbach: Although the main focus of his research was the structure, function, and regulation of mitochondrial cytochrome c oxidase (CytOx), he earlier studied the mitochondrial phosphate carrier and found an essential role of cardiolipin. Later, he discovered tissue-specific and developmental-specific protein isoforms of CytOx. Defective activity of CytOx is found with increasing age in human muscle and neuronal cells resulting in mitochondrial diseases. Kadenbach proposed a theory on the cause of oxidative stress, aging, and associated diseases stating that allosteric feedback inhibition of CytOx at high mitochondrial ATP/ADP ratios is essential for healthy living while stress-induced reversible dephosphorylation of CytOx results in the formation of excessive reactive oxygen species that trigger degenerative diseases. This article summarizes the main discoveries of Kadenbach related to mammalian CytOx and discusses their implications for human disease., (Copyright © 2021 Elsevier B.V. and Mitochondria Research Society. All rights reserved.)
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- 2021
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19. Molecular mechanisms regulating lysophosphatidylcholine acyltransferase 1 (LPCAT1) in human pregnancy.
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Purandare N, Minchella P, Somayajulu M, Kramer KJ, Zhou J, Adekoya N, Welch RA, Grossman LI, Aras S, and Recanati MA
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- 1-Acylglycerophosphocholine O-Acyltransferase genetics, Cell Line, Cell Nucleus metabolism, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, Female, Humans, Mitochondria genetics, Pregnancy, Pregnancy Trimester, Third genetics, Transcription Factors genetics, Transcription Factors metabolism, 1-Acylglycerophosphocholine O-Acyltransferase metabolism, Gene Expression Regulation, Mitochondria metabolism, Placenta metabolism, Pregnancy Trimester, Third metabolism
- Abstract
Introduction: Lysophosphatidylcholine Acyltransferase 1 (LPCAT1) is necessary for surfactant production in fetal lungs. Mechanisms responsible for its regulation during gestation remain to be elucidated. Our goal is to evaluate molecular mechanisms regulating LPCAT1 expression during gestation and after glucocorticoid administration., Methods: Placentas throughout gestation were assayed for LPCAT1 protein levels. A placental cell line, HTR-8/SVneo (HTR), was used as a model to test the effects of placental oxygen tension found during pregnancy as well as the effects of dexamethasone used therapeutically in the clinic., Results: LPCAT1 protein levels are maximal in late third trimester placental samples and are expressed strongly on the basal plate. LPCAT1 was maximally upregulated at 4% O
2 (P < 0.01), corresponding to oxygen tension found in placenta at term. Mitochondrial nuclear retrograde regulator 1 (MNRR1), a bi-organellar (mitochondria and nucleus) regulator, transcriptionally activates LPCAT1. Antenatal corticosteroids (ACS) upregulate LPCAT1, at least in part, by an MNRR1-dependent pathway. HTR cells treated with 25 nM dexamethasone for 24 h exhibited a 2-fold increase in LPCAT1 levels compared to controls. In MNRR1 knockout cells, the response to ACS is significantly blunted., Discussion: LPCAT1 appears to be induced by MNRR1. Hypoxia and corticosteroids increase LPCAT1 expression through an MNRR1 dependent pathway. LPCAT1 protein levels can be measured in maternal plasma and rise throughout gestation and in response to ACS., (Copyright © 2021 Elsevier Ltd. All rights reserved.)- Published
- 2021
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20. Regulation of COX Assembly and Function by Twin CX 9 C Proteins-Implications for Human Disease.
- Author
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Gladyck S, Aras S, Hüttemann M, and Grossman LI
- Subjects
- Amino Acid Motifs, Amino Acid Sequence, Humans, Phylogeny, Protein Binding, Protein Subunits chemistry, Protein Subunits metabolism, Disease, Electron Transport Complex IV chemistry, Electron Transport Complex IV metabolism
- Abstract
Oxidative phosphorylation is a tightly regulated process in mammals that takes place in and across the inner mitochondrial membrane and consists of the electron transport chain and ATP synthase. Complex IV, or cytochrome c oxidase (COX), is the terminal enzyme of the electron transport chain, responsible for accepting electrons from cytochrome c , pumping protons to contribute to the gradient utilized by ATP synthase to produce ATP, and reducing oxygen to water. As such, COX is tightly regulated through numerous mechanisms including protein-protein interactions. The twin CX
9 C family of proteins has recently been shown to be involved in COX regulation by assisting with complex assembly, biogenesis, and activity. The twin CX9 C motif allows for the import of these proteins into the intermembrane space of the mitochondria using the redox import machinery of Mia40/CHCHD4. Studies have shown that knockdown of the proteins discussed in this review results in decreased or completely deficient aerobic respiration in experimental models ranging from yeast to human cells, as the proteins are conserved across species. This article highlights and discusses the importance of COX regulation by twin CX9 C proteins in the mitochondria via COX assembly and control of its activity through protein-protein interactions, which is further modulated by cell signaling pathways. Interestingly, select members of the CX9 C protein family, including MNRR1 and CHCHD10, show a novel feature in that they not only localize to the mitochondria but also to the nucleus, where they mediate oxygen- and stress-induced transcriptional regulation, opening a new view of mitochondrial-nuclear crosstalk and its involvement in human disease., Competing Interests: The authors declare no conflict of interest. The funders had no role in the collection, analyses or interpretation of data; in the writing of the manuscript, or in the decision to publish the review.- Published
- 2021
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21. Mitochondrial Nuclear Retrograde Regulator 1 (MNRR1) rescues the cellular phenotype of MELAS by inducing homeostatic mechanisms.
- Author
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Aras S, Purandare N, Gladyck S, Somayajulu-Nitu M, Zhang K, Wallace DC, and Grossman LI
- Subjects
- Activating Transcription Factors metabolism, Autophagy genetics, Cell Fractionation, Cell Respiration genetics, DNA-Binding Proteins genetics, Gene Knockout Techniques, HEK293 Cells, Humans, MELAS Syndrome genetics, Mitochondria genetics, Mutation, Oxygen metabolism, Transcription Factors genetics, Unfolded Protein Response genetics, Cell Nucleus metabolism, DNA, Mitochondrial genetics, DNA-Binding Proteins metabolism, MELAS Syndrome pathology, Mitochondria metabolism, Transcription Factors metabolism
- Abstract
MNRR1 (CHCHD2) is a bi-organellar regulator of mitochondrial function that directly activates cytochrome c oxidase in the mitochondria and functions in the nucleus as a transcriptional activator for hundreds of genes. Since MNRR1 depletion contains features of a mitochondrial disease phenotype, we evaluated the effects of forced expression of MNRR1 on the mitochondrial disease MELAS (mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes) syndrome. MELAS is a multisystem encephalomyopathy disorder that can result from a heteroplasmic mutation in the mitochondrial DNA (mtDNA; m.3243A > G) at heteroplasmy levels of ∼50 to 90%. Since cybrid cell lines with 73% m.3243A > G heteroplasmy (DW7) display a significant reduction in MNRR1 levels compared to the wild type (0% heteroplasmy) (CL9), we evaluated the effects of MNRR1 levels on mitochondrial functioning. Overexpression of MNRR1 in DW7 cells induces the mitochondrial unfolded protein response (UPR
mt ), autophagy, and mitochondrial biogenesis, thereby rescuing the mitochondrial phenotype. It does so primarily as a transcription activator, revealing this function to be a potential therapeutic target. The role of MNRR1 in stimulating UPRmt , which is blunted in MELAS cells, was surprising and further investigation uncovered that under conditions of stress the import of MNRR1 into the mitochondria was blocked, allowing the protein to accumulate in the nucleus to enhance its transcription function. In the mammalian system, ATF5, has been identified as a mediator of UPRmt MNRR1 knockout cells display an ∼40% reduction in the protein levels of ATF5, suggesting that MNRR1 plays an important role upstream of this known mediator of UPRmt ., Competing Interests: Competing interest statement: Company associations for D.C.W. not related to the manuscript include MitoCURia, Mitrios, and Panos.- Published
- 2020
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22. Mitochondria Autoimmunity and MNRR1 in Breast Carcinogenesis: A Review.
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Madrid FF, Grossman LI, and Aras S
- Abstract
We review here the evidence for participation of mitochondrial autoimmunity in BC inception and progression and propose a new paradigm that may challenge the prevailing thinking in oncogenesis by suggesting that mitochondrial autoimmunity is a major contributor to breast carcinogenesis and probably to the inception and progression of other solid tumors. It has been shown that MNRR1 mediated mitochondrial-nuclear function promotes BC cell growth and migration and the development of metastasis and constitutes a proof of concept supporting the participation of mitochondrial autoimmunity in breast carcinogenesis. The resemblance of the autoantibody profile in BC detected by IFA with that in the rheumatic autoimmune diseases suggested that studies on the autoantibody response to tumor associated antigens and the characterization of the mtDNA- and nDNA-encoded antigens may provide functional data on breast carcinogenesis. We also review the studies supporting the view that a panel of autoreactive nDNA-encoded mitochondrial antigens in addition to MNRR1 may be involved in breast carcinogenesis. These include GAPDH, PKM2, GSTP1, SPATA5, MFF, ncRNA PINK1-AS/DDOST as probably contributing to BC progression and metastases and the evidence suggesting that DDX21 orchestrates a complex signaling network with participation of JUND and ATF3 driving chronic inflammation and breast tumorigenesis. We suggest that the widespread autoreactivity of mtDNA- and nDNA-encoded mitochondrial proteins found in BC sera may be the reflection of autoimmunity triggered by mitochondrial and non-mitochondrial tumor associated antigens involved in multiple tumorigenic pathways. Furthermore, we suggest that mitochondrial proteins may contribute to mitochondrial dysfunction in BC even if mitochondrial respiration is found to be within normal limits. However, although the studies show that mitochondrial autoimmunity is a major factor in breast cancer inception and progression, it is not the only factor since there is a multiplex autoantibody profile targeting centrosome and stem cell antigens as well as anti-idiotypic antibodies, revealing the complex signaling network involved in breast carcinogenesis. In summary, the studies reviewed here open new, unexpected therapeutic avenues for cancer prevention and treatment of patients with cancer derived from an entirely new perspective of breast carcinogenesis.
- Published
- 2020
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23. Cytochrome c phosphorylation: Control of mitochondrial electron transport chain flux and apoptosis.
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Kalpage HA, Wan J, Morse PT, Zurek MP, Turner AA, Khobeir A, Yazdi N, Hakim L, Liu J, Vaishnav A, Sanderson TH, Recanati MA, Grossman LI, Lee I, Edwards BFP, and Hüttemann M
- Subjects
- Apoptosis, Humans, Phosphorylation, Cytochromes c metabolism, Electron Transport genetics
- Abstract
Cytochrome c (Cytc)
1 is a cellular life and death decision molecule that regulates cellular energy supply and apoptosis through tissue specific post-translational modifications. Cytc is an electron carrier in the mitochondrial electron transport chain (ETC) and thus central for aerobic energy production. Under conditions of cellular stress, Cytc release from the mitochondria is a committing step for apoptosis, leading to apoptosome formation, caspase activation, and cell death. Recently, Cytc was shown to be a target of cellular signaling pathways that regulate the functions of Cytc by tissue-specific phosphorylations. So far five phosphorylation sites of Cytc have been mapped and functionally characterized, Tyr97, Tyr48, Thr28, Ser47, and Thr58. All five phosphorylations partially inhibit respiration, which we propose results in optimal intermediate mitochondrial membrane potentials and low ROS production under normal conditions. Four of the phosphorylations result in inhibition of the apoptotic functions of Cytc, suggesting a cytoprotective role for phosphorylated Cytc. Interestingly, these phosphorylations are lost during stress conditions such as ischemia. This results in maximal ETC flux during reperfusion, mitochondrial membrane potential hyperpolarization, excessive ROS generation, and apoptosis. We here present a new model proposing that the electron transfer from Cytc to cytochrome c oxidase is the rate-limiting step of the ETC, which is regulated via post-translational modifications of Cytc. This regulation may be dysfunctional in disease conditions such as ischemia-reperfusion injury and neurodegenerative disorders through increased ROS, or cancer, where post-translational modifications on Cytc may provide a mechanism to evade apoptosis., (Copyright © 2020 Elsevier Ltd. All rights reserved.)- Published
- 2020
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24. Decreased membrane cholesterol in liver mitochondria of the point mutation mouse model of juvenile Niemann-Pick C1, Npc1 nmf164 .
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Erickson RP, Aras S, Purandare N, Hüttemann M, Liu J, Dragotto J, Fiorenza MT, and Grossman LI
- Subjects
- Animals, Disease Models, Animal, Electron Transport Complex IV metabolism, Female, Liver metabolism, Male, Mice, Niemann-Pick C1 Protein, Niemann-Pick Disease, Type C pathology, Cell Membrane metabolism, Cholesterol analysis, DNA-Binding Proteins metabolism, Intracellular Signaling Peptides and Proteins metabolism, Mitochondria, Liver metabolism, Niemann-Pick Disease, Type C genetics, Transcription Factors metabolism
- Abstract
It has long been known that there is decreased mitochondrial function in several tissues of Niemann-Pick C1 model mice and cultured cells. These defects contribute to the accumulation of Reactive Oxygen Species (ROS) and tissue damage. It is also well established that there is increased unesterified cholesterol, stored in late endosomes/lysosomes, in many tissues in mutant humans, mouse models, and mutant cultured cells. Using a mouse model with an NPC1 point mutation that is more typical of the most common form of the disease, and highly purified liver mitochondria, we find markedly decreased mitochondrial membrane cholesterol. This is compared to previous reports of increased mitochondrial membrane cholesterol. We also find that, although in wild-type or heterozygous mitochondria cytochrome c oxidase (COX) activity decreases with age as expected, surprisingly, COX activity in homozygous mutant mice improves with age. COX activity is less than half of wild-type amounts in young mutant mice but later reaches wild-type levels while total liver cholesterol is decreasing. Mutant mice also contain a decreased number of mitochondria that are morphologically abnormal. We suggest that the decreased mitochondrial membrane cholesterol is causative for the mitochondrial energy defects. In addition, we find that the mitochondrial stress regulator protein MNRR1 can stimulate NPC1 synthesis and is deficient in mutant mouse livers. Furthermore, the age curve of MNRR1 deficiency paralleled levels of total cholesterol. The role of such altered mitochondria in initiating the abnormal autophagy and neuroinflammation found in NPC1 mouse models is discussed., (Copyright © 2019. Published by Elsevier B.V.)
- Published
- 2020
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25. Acute O 2 sensing through HIF2α-dependent expression of atypical cytochrome oxidase subunits in arterial chemoreceptors.
- Author
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Moreno-Domínguez A, Ortega-Sáenz P, Gao L, Colinas O, García-Flores P, Bonilla-Henao V, Aragonés J, Hüttemann M, Grossman LI, Weissmann N, Sommer N, and López-Barneo J
- Subjects
- Animals, Arteries cytology, Basic Helix-Loop-Helix Transcription Factors genetics, Carotid Body cytology, Carotid Body metabolism, Electron Transport Complex IV genetics, Hypoxia, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Mitochondria metabolism, Oxygen metabolism, Reactive Oxygen Species metabolism, Respiratory System metabolism, Signal Transduction, Arteries metabolism, Basic Helix-Loop-Helix Transcription Factors metabolism, Chemoreceptor Cells metabolism, Electron Transport Complex IV metabolism
- Abstract
Acute cardiorespiratory responses to O
2 deficiency are essential for physiological homeostasis. The prototypical acute O2 -sensing organ is the carotid body, which contains glomus cells expressing K+ channels whose inhibition by hypoxia leads to transmitter release and activation of nerve fibers terminating in the brainstem respiratory center. The mechanism by which changes in O2 tension modulate ion channels has remained elusive. Glomus cells express genes encoding HIF2α ( Epas1 ) and atypical mitochondrial subunits at high levels, and mitochondrial NADH and reactive oxygen species (ROS) accumulation during hypoxia provides the signal that regulates ion channels. We report that inactivation of Epas1 in adult mice resulted in selective abolition of glomus cell responsiveness to acute hypoxia and the hypoxic ventilatory response. Epas1 deficiency led to the decreased expression of atypical mitochondrial subunits in the carotid body, and genetic deletion of Cox4i2 mimicked the defective hypoxic responses of Epas1 -null mice. These findings provide a mechanistic explanation for the acute O2 regulation of breathing, reveal an unanticipated role of HIF2α, and link acute and chronic adaptive responses to hypoxia., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)- Published
- 2020
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26. Serine-47 phosphorylation of cytochrome c in the mammalian brain regulates cytochrome c oxidase and caspase-3 activity.
- Author
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Kalpage HA, Vaishnav A, Liu J, Varughese A, Wan J, Turner AA, Ji Q, Zurek MP, Kapralov AA, Kagan VE, Brunzelle JS, Recanati MA, Grossman LI, Sanderson TH, Lee I, Salomon AR, Edwards BFP, and Hüttemann M
- Subjects
- Animals, Apoptosis, Caspase 3 genetics, Cell Respiration, Crystallography, X-Ray, Cytochromes c chemistry, Cytochromes c genetics, Electron Transport Complex IV genetics, Membrane Potential, Mitochondrial, Molecular Dynamics Simulation, Mutagenesis, Site-Directed, Mutation, Oxidation-Reduction, Phosphorylation, Protein Conformation, Reactive Oxygen Species metabolism, Reperfusion Injury pathology, Serine chemistry, Serine genetics, Swine, Brain metabolism, Caspase 3 metabolism, Cytochromes c metabolism, Electron Transport Complex IV metabolism, Mitochondria metabolism, Reperfusion Injury metabolism, Serine metabolism
- Abstract
Cytochrome c (Cyt c ) is a multifunctional protein that operates as an electron carrier in the mitochondrial electron transport chain and plays a key role in apoptosis. We have previously shown that tissue-specific phosphorylations of Cyt c in the heart, liver, and kidney play an important role in the regulation of cellular respiration and cell death. Here, we report that Cyt c purified from mammalian brain is phosphorylated on S47 and that this phosphorylation is lost during ischemia. We have characterized the functional effects in vitro using phosphorylated Cyt c purified from pig brain tissue and a recombinant phosphomimetic mutant (S47E). We crystallized S47E phosphomimetic Cyt c at 1.55 Å and suggest that it spatially matches S47-phosphorylated Cyt c , making it a good model system. Both S47-phosphorylated and phosphomimetic Cyt c showed a lower oxygen consumption rate in reaction with isolated Cyt c oxidase, which we propose maintains intermediate mitochondrial membrane potentials under physiologic conditions, thus minimizing production of reactive oxygen species. S47-phosphorylated and phosphomimetic Cyt c showed lower caspase-3 activity. Furthermore, phosphomimetic Cyt c had decreased cardiolipin peroxidase activity and is more stable in the presence of H
2 O2 . Our data suggest that S47 phosphorylation of Cyt c is tissue protective and promotes cell survival in the brain.-Kalpage, H. A., Vaishnav, A., Liu, J., Varughese, A., Wan, J., Turner, A. A., Ji, Q., Zurek, M. P., Kapralov, A. A., Kagan, V. E., Brunzelle, J. S., Recanati, M.-A., Grossman, L. I., Sanderson, T. H., Lee, I., Salomon, A. R., Edwards, B. F. P, Hüttemann, M. Serine-47 phosphorylation of cytochrome c in the mammalian brain regulates cytochrome c oxidase and caspase-3 activity.- Published
- 2019
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27. Regulation of Respiration and Apoptosis by Cytochrome c Threonine 58 Phosphorylation.
- Author
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Wan J, Kalpage HA, Vaishnav A, Liu J, Lee I, Mahapatra G, Turner AA, Zurek MP, Ji Q, Moraes CT, Recanati MA, Grossman LI, Salomon AR, Edwards BFP, and Hüttemann M
- Subjects
- Amino Acid Sequence, Animals, Cytochromes c chemistry, Humans, Mice, Phosphorylation, Apoptosis, Cytochromes c metabolism, Threonine metabolism
- Abstract
Cytochrome c (Cytc) is a multifunctional protein, acting as an electron carrier in the electron transport chain (ETC), where it shuttles electrons from bc
1 complex to cytochrome c oxidase (COX), and as a trigger of type II apoptosis when released from the mitochondria. We previously showed that Cytc is regulated in a highly tissue-specific manner: Cytc isolated from heart, liver, and kidney is phosphorylated on Y97, Y48, and T28, respectively. Here, we have analyzed the effect of a new Cytc phosphorylation site, threonine 58, which we mapped in rat kidney Cytc by mass spectrometry. We generated and overexpressed wild-type, phosphomimetic T58E, and two controls, T58A and T58I Cytc; the latter replacement is found in human and testis-specific Cytc. In vitro, COX activity, caspase-3 activity, and heme degradation in the presence of H2 O2 were decreased with phosphomimetic Cytc compared to wild-type. Cytc-knockout cells expressing T58E or T58I Cytc showed a reduction in intact cell respiration, mitochondrial membrane potential (∆Ψm ), ROS production, and apoptotic activity compared to wild-type. We propose that, under physiological conditions, Cytc is phosphorylated, which controls mitochondrial respiration and apoptosis. Under conditions of stress Cytc phosphorylations are lost leading to maximal respiration rates, ∆Ψm hyperpolarization, ROS production, and apoptosis.- Published
- 2019
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28. Letter by Hüttemann et al Regarding Article, "Ndufs2, a Core Subunit of Mitochondrial Complex I, Is Essential for Acute Oxygen-Sensing and Hypoxic Pulmonary Vasoconstriction".
- Author
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Hüttemann M, Sommer N, Weissmann N, and Grossman LI
- Subjects
- Humans, Hypoxia, Lung, NADH Dehydrogenase, Oxygen, Vasoconstriction
- Published
- 2019
- Full Text
- View/download PDF
29. Mitochondrial autoimmunity and MNRR1 in breast carcinogenesis.
- Author
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Aras S, Maroun MC, Song Y, Bandyopadhyay S, Stark A, Yang ZQ, Long MP, Grossman LI, and Fernández-Madrid F
- Subjects
- Autoantigens metabolism, Autoimmunity, Breast Neoplasms genetics, Breast Neoplasms metabolism, Carcinoma, Ductal, Breast metabolism, Cell Line, Tumor, Cell Movement, Cell Proliferation, DNA-Binding Proteins, Female, Gene Expression Regulation, Neoplastic, Humans, MCF-7 Cells, Mitochondria genetics, Neoplasm Invasiveness, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha genetics, Prospective Studies, Protein Array Analysis, Rapamycin-Insensitive Companion of mTOR Protein genetics, Up-Regulation, Breast Neoplasms diagnosis, Carcinoma, Ductal, Breast diagnosis, Mitochondria metabolism, Mitochondrial Proteins genetics, Mitochondrial Proteins metabolism, Transcription Factors genetics, Transcription Factors metabolism
- Abstract
Background: Autoantibodies function as markers of tumorigenesis and have been proposed to enhance early detection of malignancies. We recently reported, using immunoscreening of a T7 complementary DNA (cDNA) library of breast cancer (BC) proteins with sera from patients with BC, the presence of autoantibodies targeting several mitochondrial DNA (mtDNA)-encoded subunits of the electron transport chain (ETC) in complexes I, IV, and V., Methods: In this study, we have characterized the role of Mitochondrial-Nuclear Retrograde Regulator 1 (MNRR1, also known as CHCHD2), identified on immunoscreening, in breast carcinogenesis. We assessed the protein as well as transcript levels of MNRR1 in BC tissues and in derived cell lines representing tumors of graded aggressiveness. Mitochondrial function was also assayed and correlated with the levels of MNRR1. We studied the invasiveness of BC derived cells and the effect of MNRR1 levels on expression of genes associated with cell proliferation and migration such as Rictor and PGC-1α. Finally, we manipulated levels of MNRR1 to assess its effect on mitochondria and on some properties linked to a metastatic phenotype., Results: We identified a nuclear DNA (nDNA)-encoded mitochondrial protein, MNRR1, that was significantly associated with the diagnosis of invasive ductal carcinoma (IDC) of the breast by autoantigen microarray analysis. In focusing on the mechanism of action of MNRR1 we found that its level was nearly twice as high in malignant versus benign breast tissue and up to 18 times as high in BC cell lines compared to MCF10A control cells, suggesting a relationship to aggressive potential. Furthermore, MNRR1 affected levels of multiple genes previously associated with cancer metastasis., Conclusions: MNRR1 regulates multiple genes that function in cell migration and cancer metastasis and is higher in cell lines derived from aggressive tumors. Since MNRR1 was identified as an autoantigen in breast carcinogenesis, the present data support our proposal that both mitochondrial autoimmunity and MNRR1 activity in particular are involved in breast carcinogenesis. Virtually all other nuclear encoded genes identified on immunoscreening of invasive BC harbor an MNRR1 binding site in their promoters, thereby placing MNRR1 upstream and potentially making it a novel marker for BC metastasis.
- Published
- 2019
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30. HIF-1α regulates IL-1β and IL-17 in sarcoidosis.
- Author
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Talreja J, Talwar H, Bauerfeld C, Grossman LI, Zhang K, Tranchida P, and Samavati L
- Subjects
- Adolescent, Adult, Female, Humans, Inflammation pathology, Lung pathology, Macrophages pathology, Male, Monocytes pathology, Th1 Cells immunology, Th17 Cells immunology, Young Adult, Gene Expression Regulation, Hypoxia-Inducible Factor 1, alpha Subunit metabolism, Interleukin-17 biosynthesis, Interleukin-1beta biosynthesis, Sarcoidosis pathology
- Abstract
Sarcoidosis is a complex systemic granulomatous disease of unknown etiology characterized by the presence of activated macrophages and Th1/Th17 effector cells. Data mining of our RNA-Seq analysis of CD14
+ monocytes showed enrichment for metabolic and hypoxia inducible factor (HIF) pathways in sarcoidosis. Further investigation revealed that sarcoidosis macrophages and monocytes exhibit higher protein levels for HIF-α isoforms, HIF-1β, and their transcriptional co-activator p300 as well as glucose transporter 1 (Glut1). In situ hybridization of sarcoidosis granulomatous lung tissues showed abundance of HIF-1α in the center of granulomas. The abundance of HIF isoforms was mechanistically linked to elevated IL-1β and IL-17 since targeted down regulation of HIF-1α via short interfering RNA or a HIF-1α inhibitor decreased their production. Pharmacological intervention using chloroquine, a lysosomal inhibitor, decreased lysosomal associated protein 2 (LAMP2) and HIF-1α levels and modified cytokine production. These data suggest that increased activity of HIF-α isoforms regulate Th1/Th17 mediated inflammation in sarcoidosis., Competing Interests: JT, HT, CB, LG, KZ, PT, LS No competing interests declared, (© 2019, Talreja et al.)- Published
- 2019
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31. Tissue-specific regulation of cytochrome c by post-translational modifications: respiration, the mitochondrial membrane potential, ROS, and apoptosis.
- Author
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Kalpage HA, Bazylianska V, Recanati MA, Fite A, Liu J, Wan J, Mantena N, Malek MH, Podgorski I, Heath EI, Vaishnav A, Edwards BF, Grossman LI, Sanderson TH, Lee I, and Hüttemann M
- Subjects
- Acetylation, Amino Acids metabolism, Animals, Cytochromes c chemistry, Humans, Methylation, Mitochondria metabolism, Nitroso Compounds metabolism, Oxidation-Reduction, Phosphorylation, Sulfides metabolism, Apoptosis, Cytochromes c metabolism, Membrane Potential, Mitochondrial, Protein Processing, Post-Translational, Reactive Oxygen Species metabolism
- Abstract
Cytochrome c (Cyt c) plays a vital role in the mitochondrial electron transport chain (ETC). In addition, it is a key regulator of apoptosis. Cyt c has multiple other functions including ROS production and scavenging, cardiolipin peroxidation, and mitochondrial protein import. Cyt c is tightly regulated by allosteric mechanisms, tissue-specific isoforms, and post-translational modifications (PTMs). Distinct residues of Cyt c are modified by PTMs, primarily phosphorylations, in a highly tissue-specific manner. These modifications downregulate mitochondrial ETC flux and adjust the mitochondrial membrane potential (ΔΨ
m ), to minimize reactive oxygen species (ROS) production under normal conditions. In pathologic and acute stress conditions, such as ischemia-reperfusion, phosphorylations are lost, leading to maximum ETC flux, ΔΨm hyperpolarization, excessive ROS generation, and the release of Cyt c. It is also the dephosphorylated form of the protein that leads to maximum caspase activation. We discuss the complex regulation of Cyt c and propose that it is a central regulatory step of the mammalian ETC that can be rate limiting in normal conditions. This regulation is important because it maintains optimal intermediate ΔΨm , limiting ROS generation. We examine the role of Cyt c PTMs, including phosphorylation, acetylation, methylation, nitration, nitrosylation, and sulfoxidation and consider their potential biological significance by evaluating their stoichiometry.-Kalpage, H. A., Bazylianska, V., Recanati, M. A., Fite, A., Liu, J., Wan, J., Mantena, N., Malek, M. H., Podgorski, I., Heath, E. I., Vaishnav, A., Edwards, B. F., Grossman, L. I., Sanderson, T. H., Lee, I., Hüttemann, M. Tissue-specific regulation of cytochrome c by post-translational modifications: respiration, the mitochondrial membrane potential, ROS, and apoptosis.- Published
- 2019
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32. What Science Journalists Wish Astrobiologists Knew About Journalism.
- Author
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Grossman LI
- Subjects
- Communication, Humans, Science, Exobiology, Journalism
- Published
- 2018
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33. The cellular stress proteins CHCHD10 and MNRR1 (CHCHD2): Partners in mitochondrial and nuclear function and dysfunction.
- Author
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Purandare N, Somayajulu M, Hüttemann M, Grossman LI, and Aras S
- Subjects
- Carrier Proteins genetics, Carrier Proteins metabolism, Cell Nucleus genetics, Cell Nucleus pathology, DNA-Binding Proteins, HEK293 Cells, HeLa Cells, Humans, Mitochondria genetics, Mitochondria pathology, Mitochondrial Proteins genetics, Oxygen Consumption, Protein-Tyrosine Kinases genetics, Protein-Tyrosine Kinases metabolism, Proto-Oncogene Mas, Reactive Oxygen Species metabolism, Transcription Factors genetics, Cell Nucleus metabolism, Mitochondria metabolism, Mitochondrial Proteins metabolism, Response Elements, Transcription Factors metabolism, Transcription, Genetic
- Abstract
Coiled-coil-helix-coiled-coil-helix domain-containing 10 (CHCHD10) and CHCHD2 (MNRR1) are homologous proteins with 58% sequence identity and belong to the twin CX
9 C family of proteins that mediate cellular stress responses. Despite the identification of several neurodegeneration-associated mutations in the CHCHD10 gene, few studies have assessed its physiological role. Here, we investigated CHCHD10's function as a regulator of oxidative phosphorylation in the mitochondria and the nucleus. We show that CHCHD10 copurifies with cytochrome c oxidase (COX) and up-regulates COX activity by serving as a scaffolding protein required for MNRR1 phosphorylation, mediated by ARG (ABL proto-oncogene 2, nonreceptor tyrosine kinase (ABL2)). The CHCHD10 gene was maximally transcribed in cultured cells at 8% oxygen, unlike MNRR1 , which was maximally expressed at 4%, suggesting a fine-tuned oxygen-sensing system that adapts to the varying oxygen concentrations in the human body under physiological conditions. We show that nuclear CHCHD10 protein down-regulates the expression of genes harboring the oxygen-responsive element (ORE) in their promoters by interacting with and augmenting the activity of the largely uncharacterized transcriptional repressor CXXC finger protein 5 (CXXC5). We further show that two genetic CHCHD10 disease variants, G66V and P80L, in the mitochondria exhibit faulty interactions with MNRR1 and COX, reducing respiration and increasing reactive oxygen species (ROS), and in the nucleus abrogating transcriptional repression of ORE-containing genes. Our results reveal that CHCHD10 positively regulates mitochondrial respiration and contributes to transcriptional repression of ORE-containing genes in the nucleus, and that genetic CHCHD10 variants are impaired in these activities., (© 2018 by The American Society for Biochemistry and Molecular Biology, Inc.)- Published
- 2018
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34. Publisher Correction: Inhibitory modulation of cytochrome c oxidase activity with specific near-infrared light wavelengths attenuates brain ischemia/reperfusion injury.
- Author
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Sanderson TH, Wider JM, Lee I, Reynolds CA, Liu J, Lepore B, Tousignant R, Bukowski MJ, Johnston H, Fite A, Raghunayakula S, Kamholz J, Grossman LI, Przyklenk K, and Hüttemann M
- Abstract
A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
- Published
- 2018
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35. Inhibitory modulation of cytochrome c oxidase activity with specific near-infrared light wavelengths attenuates brain ischemia/reperfusion injury.
- Author
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Sanderson TH, Wider JM, Lee I, Reynolds CA, Liu J, Lepore B, Tousignant R, Bukowski MJ, Johnston H, Fite A, Raghunayakula S, Kamholz J, Grossman LI, Przyklenk K, and Hüttemann M
- Subjects
- Animals, Brain pathology, Brain radiation effects, Brain Injuries genetics, Brain Injuries pathology, Electron Transport Complex IV radiation effects, Glucose metabolism, Hippocampus metabolism, Hippocampus pathology, Hippocampus radiation effects, Humans, Membrane Potential, Mitochondrial, Mitochondria genetics, Mitochondria radiation effects, Neurons metabolism, Neurons radiation effects, Oxidation-Reduction radiation effects, Rats, Reperfusion Injury genetics, Reperfusion Injury pathology, Brain Injuries radiotherapy, Electron Transport Complex IV genetics, Infrared Rays therapeutic use, Reperfusion Injury radiotherapy
- Abstract
The interaction of light with biological tissue has been successfully utilized for multiple therapeutic purposes. Previous studies have suggested that near infrared light (NIR) enhances the activity of mitochondria by increasing cytochrome c oxidase (COX) activity, which we confirmed for 810 nm NIR. In contrast, scanning the NIR spectrum between 700 nm and 1000 nm revealed two NIR wavelengths (750 nm and 950 nm) that reduced the activity of isolated COX. COX-inhibitory wavelengths reduced mitochondrial respiration, reduced the mitochondrial membrane potential (ΔΨ
m ), attenuated mitochondrial superoxide production, and attenuated neuronal death following oxygen glucose deprivation, whereas NIR that activates COX provided no benefit. We evaluated COX-inhibitory NIR as a potential therapy for cerebral reperfusion injury using a rat model of global brain ischemia. Untreated animals demonstrated an 86% loss of neurons in the CA1 hippocampus post-reperfusion whereas inhibitory NIR groups were robustly protected, with neuronal loss ranging from 11% to 35%. Moreover, neurologic function, assessed by radial arm maze performance, was preserved at control levels in rats treated with a combination of both COX-inhibitory NIR wavelengths. Taken together, our data suggest that COX-inhibitory NIR may be a viable non-pharmacologic and noninvasive therapy for the treatment of cerebral reperfusion injury.- Published
- 2018
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36. Metformin, the aspirin of the 21st century: its role in gestational diabetes mellitus, prevention of preeclampsia and cancer, and the promotion of longevity.
- Author
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Romero R, Erez O, Hüttemann M, Maymon E, Panaitescu B, Conde-Agudelo A, Pacora P, Yoon BH, and Grossman LI
- Subjects
- Diabetes, Gestational drug therapy, Female, Fetal Development, Humans, Hypoglycemic Agents pharmacology, Longevity, Maternal Nutritional Physiological Phenomena, Maternal-Fetal Exchange, Metformin pharmacology, Neoplasms prevention & control, Pre-Eclampsia prevention & control, Pregnancy, Randomized Controlled Trials as Topic, TOR Serine-Threonine Kinases metabolism, Hypoglycemic Agents therapeutic use, Metformin therapeutic use
- Abstract
Metformin is everywhere. Originally introduced in clinical practice as an antidiabetic agent, its role as a therapeutic agent is expanding to include treatment of prediabetes mellitus, gestational diabetes mellitus, and polycystic ovarian disease; more recently, experimental studies and observations in randomized clinical trials suggest that metformin could have a place in the treatment or prevention of preeclampsia. This article provides a brief overview of the history of metformin in the treatment of diabetes mellitus and reviews the results of metaanalyses of metformin in gestational diabetes mellitus as well as the treatment of obese, non-diabetic, pregnant women to prevent macrosomia. We highlight the results of a randomized clinical trial in which metformin administration in early pregnancy did not reduce the frequency of large-for-gestational-age infants (the primary endpoint) but did decrease the frequency of preeclampsia (a secondary endpoint). The mechanisms by which metformin may prevent preeclampsia include a reduction in the production of antiangiogenic factors (soluble vascular endothelial growth factor receptor-1 and soluble endoglin) and the improvement of endothelial dysfunction, probably through an effect on the mitochondria. Another potential mechanism whereby metformin may play a role in the prevention of preeclampsia is its ability to modify cellular homeostasis and energy disposition, mediated by rapamycin, a mechanistic target. Metformin has a molecular weight of 129 Daltons and therefore readily crosses the placenta. There is considerable evidence to suggest that this agent is safe during pregnancy. New literature on the role of metformin as a chemotherapeutic adjuvant in the prevention of cancer and in prolonging life and protecting against aging is reviewed briefly. Herein, we discuss the mechanisms of action and potential benefits of metformin., (Published by Elsevier Inc.)
- Published
- 2017
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37. Mitochondrial Complex IV Subunit 4 Isoform 2 Is Essential for Acute Pulmonary Oxygen Sensing.
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Sommer N, Hüttemann M, Pak O, Scheibe S, Knoepp F, Sinkler C, Malczyk M, Gierhardt M, Esfandiary A, Kraut S, Jonas F, Veith C, Aras S, Sydykov A, Alebrahimdehkordi N, Giehl K, Hecker M, Brandes RP, Seeger W, Grimminger F, Ghofrani HA, Schermuly RT, Grossman LI, and Weissmann N
- Subjects
- Animals, Cell Hypoxia physiology, Cell Line, Tumor, Electron Transport Complex IV genetics, Female, Humans, Male, Membrane Potential, Mitochondrial physiology, Mice, Mice, Knockout, Mitochondria genetics, Electron Transport Complex IV metabolism, Lung metabolism, Mitochondria metabolism, Oxygen metabolism
- Abstract
Rationale: Acute pulmonary oxygen sensing is essential to avoid life-threatening hypoxemia via hypoxic pulmonary vasoconstriction (HPV) which matches perfusion to ventilation. Hypoxia-induced mitochondrial superoxide release has been suggested as a critical step in the signaling pathway underlying HPV. However, the identity of the primary oxygen sensor and the mechanism of superoxide release in acute hypoxia, as well as its relevance for chronic pulmonary oxygen sensing, remain unresolved., Objectives: To investigate the role of the pulmonary-specific isoform 2 of subunit 4 of the mitochondrial complex IV (Cox4i2) and the subsequent mediators superoxide and hydrogen peroxide for pulmonary oxygen sensing and signaling., Methods and Results: Isolated ventilated and perfused lungs from Cox4i2
-/- mice lacked acute HPV. In parallel, pulmonary arterial smooth muscle cells (PASMCs) from Cox4i2-/- mice showed no hypoxia-induced increase of intracellular calcium. Hypoxia-induced superoxide release which was detected by electron spin resonance spectroscopy in wild-type PASMCs was absent in Cox4i2-/- PASMCs and was dependent on cysteine residues of Cox4i2. HPV could be inhibited by mitochondrial superoxide inhibitors proving the functional relevance of superoxide release for HPV. Mitochondrial hyperpolarization, which can promote mitochondrial superoxide release, was detected during acute hypoxia in wild-type but not Cox4i2-/- PASMCs. Downstream signaling determined by patch-clamp measurements showed decreased hypoxia-induced cellular membrane depolarization in Cox4i2-/- PASMCs compared with wild-type PASMCs, which could be normalized by the application of hydrogen peroxide. In contrast, chronic hypoxia-induced pulmonary hypertension and pulmonary vascular remodeling were not or only slightly affected by Cox4i2 deficiency, respectively., Conclusions: Cox4i2 is essential for acute but not chronic pulmonary oxygen sensing by triggering mitochondrial hyperpolarization and release of mitochondrial superoxide which, after conversion to hydrogen peroxide, contributes to cellular membrane depolarization and HPV. These findings provide a new model for oxygen-sensing processes in the lung and possibly also in other organs., (© 2017 American Heart Association, Inc.)- Published
- 2017
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38. Divergent lactate dehydrogenase isoenzyme profile in cellular compartments of primate forebrain structures.
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Duka T, Collins Z, Anderson SM, Raghanti MA, Ely JJ, Hof PR, Wildman DE, Goodman M, Grossman LI, and Sherwood CC
- Subjects
- Animals, Corpus Striatum metabolism, Female, Isoenzymes metabolism, Lactate Dehydrogenase 5, Male, Primates, Synaptosomes metabolism, L-Lactate Dehydrogenase metabolism, Mitochondria metabolism, Neocortex metabolism
- Abstract
The compartmentalization and association of lactate dehydrogenase (LDH) with specific cellular structures (e.g., synaptosomal, sarcoplasmic or mitochondrial) may play an important role in brain energy metabolism. Our previous research revealed that LDH in the synaptosomal fraction shifts toward the aerobic isoforms (LDH-B) among the large-brained haplorhine primates compared to strepsirrhines. Here, we further analyzed the subcellular localization of LDH in primate forebrain structures using quantitative Western blotting and ELISA. We show that, in cytosolic and mitochondrial subfractions, LDH-B expression level was relatively elevated and LDH-A declined in haplorhines compared to strepsirrhines. LDH-B expression in mitochondrial fractions of the neocortex was preferentially increased, showing a particularly significant rise in the ratio of LDH-B to LDH-A in chimpanzees and humans. We also found a significant correlation between the protein levels of LDH-B in mitochondrial fractions from haplorhine neocortex and the synaptosomal LDH-B that suggests LDH isoforms shift from a predominance of A-subunits toward B-subunits as part of a system that spatially buffers dynamic energy requirements of brain cells. Our results indicate that there is differential subcellular compartmentalization of LDH isoenzymes that evolved among different primate lineages to meet the energy requirements in neocortical and striatal cells., (Copyright © 2017 Elsevier Inc. All rights reserved.)
- Published
- 2017
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39. Abl2 kinase phosphorylates Bi-organellar regulator MNRR1 in mitochondria, stimulating respiration.
- Author
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Aras S, Arrabi H, Purandare N, Hüttemann M, Kamholz J, Züchner S, and Grossman LI
- Subjects
- Adenosine Triphosphate metabolism, Cell Line, Charcot-Marie-Tooth Disease genetics, DNA-Binding Proteins, Female, Humans, Middle Aged, Mitochondrial Proteins genetics, Mutation, Oxidative Phosphorylation, Reactive Oxygen Species metabolism, Transcription Factors genetics, Cell Respiration, Mitochondria metabolism, Mitochondrial Proteins metabolism, Protein-Tyrosine Kinases metabolism, Transcription Factors metabolism
- Abstract
We previously showed that MNRR1 (Mitochondrial Nuclear Retrograde Regulator 1, also CHCHD2) functions in two subcellular compartments, displaying a different function in each. In the mitochondria it is a stress regulator of respiration that binds to cytochrome c oxidase (COX) whereas in the nucleus it is a transactivator of COX4I2 and other hypoxia-stimulated genes. We now show that binding of MNRR1 to COX is promoted by phosphorylation at tyrosine-99 and that this interaction stimulates respiration. We show that phosphorylation of MNRR1 takes place in mitochondria and is mediated by Abl2 kinase (ARG). A family with Charcot-Marie-Tooth disease type 1A with an exaggerated phenotype harbors a Q112H mutation in MNRR1, located in a domain that is necessary for transcriptional activation by MNRR1. Furthermore, the mutation causes the protein to function suboptimally in the mitochondria in response to cellular stress. The Q112H mutation hinders the ability of the protein to interact with Abl kinase, leading to defective tyrosine phosphorylation and a resultant defect in respiration., (Copyright © 2016 Elsevier B.V. All rights reserved.)
- Published
- 2017
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40. Phosphorylation of Cytochrome c Threonine 28 Regulates Electron Transport Chain Activity in Kidney: IMPLICATIONS FOR AMP KINASE.
- Author
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Mahapatra G, Varughese A, Ji Q, Lee I, Liu J, Vaishnav A, Sinkler C, Kapralov AA, Moraes CT, Sanderson TH, Stemmler TL, Grossman LI, Kagan VE, Brunzelle JS, Salomon AR, Edwards BF, and Hüttemann M
- Subjects
- Adenylate Kinase chemistry, Animals, Apoptosis, Crystallography, X-Ray, Cytochromes c chemistry, Electron Transport, Electron Transport Complex IV chemistry, Kidney cytology, Membrane Potential, Mitochondrial, Mice, Mitochondria metabolism, Oxidation-Reduction, Phosphorylation, Protein Conformation, Reactive Oxygen Species metabolism, Adenylate Kinase metabolism, Cell Respiration physiology, Cytochromes c metabolism, Electron Transport Complex IV metabolism, Kidney metabolism, Threonine metabolism
- Abstract
Mammalian cytochrome c (Cytc) plays a key role in cellular life and death decisions, functioning as an electron carrier in the electron transport chain and as a trigger of apoptosis when released from the mitochondria. However, its regulation is not well understood. We show that the major fraction of Cytc isolated from kidneys is phosphorylated on Thr
28 , leading to a partial inhibition of respiration in the reaction with cytochrome c oxidase. To further study the effect of Cytc phosphorylation in vitro, we generated T28E phosphomimetic Cytc, revealing superior behavior regarding protein stability and its ability to degrade reactive oxygen species compared with wild-type unphosphorylated Cytc Introduction of T28E phosphomimetic Cytc into Cytc knock-out cells shows that intact cell respiration, mitochondrial membrane potential (ΔΨm ), and ROS levels are reduced compared with wild type. As we show by high resolution crystallography of wild-type and T28E Cytc in combination with molecular dynamics simulations, Thr28 is located at a central position near the heme crevice, the most flexible epitope of the protein apart from the N and C termini. Finally, in silico prediction and our experimental data suggest that AMP kinase, which phosphorylates Cytc on Thr28 in vitro and colocalizes with Cytc to the mitochondrial intermembrane space in the kidney, is the most likely candidate to phosphorylate Thr28 in vivo We conclude that Cytc phosphorylation is mediated in a tissue-specific manner and leads to regulation of electron transport chain flux via "controlled respiration," preventing ΔΨm hyperpolarization, a known cause of ROS and trigger of apoptosis., (© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.)- Published
- 2017
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41. MNRR1, a Biorganellar Regulator of Mitochondria.
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Grossman LI, Purandare N, Arshad R, Gladyck S, Somayajulu M, Hüttemann M, and Aras S
- Subjects
- Animals, DNA-Binding Proteins, Electron Transport Complex IV metabolism, Humans, Mitochondrial Proteins genetics, Protein Binding, Transcription Factors genetics, Mitochondria metabolism, Mitochondrial Proteins metabolism, Transcription Factors metabolism
- Abstract
The central role of energy metabolism in cellular activities is becoming widely recognized. However, there are many gaps in our knowledge of the mechanisms by which mitochondria evaluate their status and call upon the nucleus to make adjustments. Recently, a protein family consisting of twin CX
9 C proteins has been shown to play a role in human pathophysiology. We focus here on two family members, the isoforms CHCHD2 (renamed MNRR1) and CHCHD10. The better studied isoform, MNRR1, has the unusual property of functioning in both the mitochondria and the nucleus and of having a different function in each. In the mitochondria, it functions by binding to cytochrome c oxidase (COX), which stimulates respiration. Its binding to COX is promoted by tyrosine-99 phosphorylation, carried out by ABL2 kinase (ARG). In the nucleus, MNRR1 binds to a novel promoter element in COX4I2 and itself, increasing transcription at 4% oxygen. We discuss mutations in both MNRR1 and CHCHD10 found in a number of chronic, mostly neurodegenerative, diseases. Finally, we propose a model of a graded response to hypoxic and oxidative stresses, mediated under different oxygen tensions by CHCHD10, MNRR1, and HIF1, which operate at intermediate and very low oxygen concentrations, respectively.- Published
- 2017
- Full Text
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42. Tissue- and Condition-Specific Isoforms of Mammalian Cytochrome c Oxidase Subunits: From Function to Human Disease.
- Author
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Sinkler CA, Kalpage H, Shay J, Lee I, Malek MH, Grossman LI, and Hüttemann M
- Subjects
- Allosteric Regulation, Electron Transport Complex IV genetics, Humans, Isoenzymes biosynthesis, Isoenzymes genetics, Organ Specificity, Electron Transport Complex IV biosynthesis, Gene Expression Regulation, Enzymologic, Signal Transduction, Thermogenesis
- Abstract
Cytochrome c oxidase (COX) is the terminal enzyme of the electron transport chain and catalyzes the transfer of electrons from cytochrome c to oxygen. COX consists of 14 subunits, three and eleven encoded, respectively, by the mitochondrial and nuclear DNA. Tissue- and condition-specific isoforms have only been reported for COX but not for the other oxidative phosphorylation complexes, suggesting a fundamental requirement to fine-tune and regulate the essentially irreversible reaction catalyzed by COX. This article briefly discusses the assembly of COX in mammals and then reviews the functions of the six nuclear-encoded COX subunits that are expressed as isoforms in specialized tissues including those of the liver, heart and skeletal muscle, lung, and testes: COX IV-1, COX IV-2, NDUFA4, NDUFA4L2, COX VIaL, COX VIaH, COX VIb-1, COX VIb-2, COX VIIaH, COX VIIaL, COX VIIaR, COX VIIIH/L, and COX VIII-3. We propose a model in which the isoforms mediate the interconnected regulation of COX by (1) adjusting basal enzyme activity to mitochondrial capacity of a given tissue; (2) allosteric regulation to adjust energy production to need; (3) altering proton pumping efficiency under certain conditions, contributing to thermogenesis; (4) providing a platform for tissue-specific signaling; (5) stabilizing the COX dimer; and (6) modulating supercomplex formation.
- Published
- 2017
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43. COX7AR is a Stress-inducible Mitochondrial COX Subunit that Promotes Breast Cancer Malignancy.
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Zhang K, Wang G, Zhang X, Hüttemann PP, Qiu Y, Liu J, Mitchell A, Lee I, Zhang C, Lee JS, Pecina P, Wu G, Yang ZQ, Hüttemann M, and Grossman LI
- Subjects
- Adenosine Triphosphate chemistry, Animals, CHO Cells, Cell Line, Tumor, Cell Proliferation, Cricetinae, Cricetulus, Energy Metabolism, Female, Fibroblasts metabolism, Fluorescent Antibody Technique, Indirect, HEK293 Cells, Humans, Mice, Mitochondrial Membranes metabolism, Neoplasm Invasiveness, Oligonucleotide Array Sequence Analysis, RNA, Small Interfering, Tissue Distribution, Breast Neoplasms genetics, Breast Neoplasms metabolism, Electron Transport Complex IV genetics, Electron Transport Complex IV metabolism, Mitochondria metabolism
- Abstract
Cytochrome c oxidase (COX), the terminal enzyme of the mitochondrial respiratory chain, plays a key role in regulating mitochondrial energy production and cell survival. COX subunit VIIa polypeptide 2-like protein (COX7AR) is a novel COX subunit that was recently found to be involved in mitochondrial supercomplex assembly and mitochondrial respiration activity. Here, we report that COX7AR is expressed in high energy-demanding tissues, such as brain, heart, liver, and aggressive forms of human breast cancer cells. Under cellular stress that stimulates energy metabolism, COX7AR is induced and incorporated into the mitochondrial COX complex. Functionally, COX7AR promotes cellular energy production in human mammary epithelial cells. Gain- and loss-of-function analysis demonstrates that COX7AR is required for human breast cancer cells to maintain higher rates of proliferation, clone formation, and invasion. In summary, our study revealed that COX7AR is a stress-inducible mitochondrial COX subunit that facilitates human breast cancer malignancy. These findings have important implications in the understanding and treatment of human breast cancer and the diseases associated with mitochondrial energy metabolism.
- Published
- 2016
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44. High-throughput RNA sequencing reveals structural differences of orthologous brain-expressed genes between western lowland gorillas and humans.
- Author
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Lipovich L, Hou ZC, Jia H, Sinkler C, McGowen M, Sterner KN, Weckle A, Sugalski AB, Pipes L, Gatti DL, Mason CE, Sherwood CC, Hof PR, Kuzawa CW, Grossman LI, Goodman M, and Wildman DE
- Subjects
- Animals, Carrier Proteins genetics, Carrier Proteins metabolism, Gene Expression Profiling, Gorilla gorilla anatomy & histology, Humans anatomy & histology, Intracellular Signaling Peptides and Proteins, Models, Molecular, Muscle Proteins genetics, Muscle Proteins metabolism, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Phosphoprotein Phosphatases genetics, Phosphoprotein Phosphatases metabolism, Phylogeny, Species Specificity, Transcription Factors genetics, Transcription Factors metabolism, beta 2-Glycoprotein I genetics, beta 2-Glycoprotein I metabolism, Brain metabolism, Gene Expression physiology, High-Throughput Nucleotide Sequencing, RNA metabolism
- Abstract
The human brain and human cognitive abilities are strikingly different from those of other great apes despite relatively modest genome sequence divergence. However, little is presently known about the interspecies divergence in gene structure and transcription that might contribute to these phenotypic differences. To date, most comparative studies of gene structure in the brain have examined humans, chimpanzees, and macaque monkeys. To add to this body of knowledge, we analyze here the brain transcriptome of the western lowland gorilla (Gorilla gorilla gorilla), an African great ape species that is phylogenetically closely related to humans, but with a brain that is approximately one-third the size. Manual transcriptome curation from a sample of the planum temporale region of the neocortex revealed 12 protein-coding genes and one noncoding-RNA gene with exons in the gorilla unmatched by public transcriptome data from the orthologous human loci. These interspecies gene structure differences accounted for a total of 134 amino acids in proteins found in the gorilla that were absent from protein products of the orthologous human genes. Proteins varying in structure between human and gorilla were involved in immunity and energy metabolism, suggesting their relevance to phenotypic differences. This gorilla neocortical transcriptome comprises an empirical, not homology- or prediction-driven, resource for orthologous gene comparisons between human and gorilla. These findings provide a unique repository of the sequences and structures of thousands of genes transcribed in the gorilla brain, pointing to candidate genes that may contribute to the traits distinguishing humans from other closely related great apes., (© 2015 Wiley Periodicals, Inc.)
- Published
- 2016
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45. The brown and brite adipocyte marker Cox7a1 is not required for non-shivering thermogenesis in mice.
- Author
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Maurer SF, Fromme T, Grossman LI, Hüttemann M, and Klingenspor M
- Subjects
- Adipocytes physiology, Adipose Tissue, Brown physiology, Animals, Cold Temperature, Diet, High-Fat, Electron Transport Complex IV genetics, Glucose metabolism, Ion Channels metabolism, Mice, Mice, Knockout, Mitochondrial Proteins metabolism, Norepinephrine metabolism, Shivering physiology, Stress, Physiological genetics, Uncoupling Protein 1, Acclimatization genetics, Adipocytes metabolism, Adipose Tissue, Brown metabolism, Electron Transport Complex IV biosynthesis, Ion Channels genetics, Mitochondrial Proteins genetics, Thermogenesis genetics
- Abstract
The cytochrome c oxidase subunit isoform Cox7a1 is highly abundant in skeletal muscle and heart and influences enzyme activity in these tissues characterised by high oxidative capacity. We identified Cox7a1, well-known as brown adipocyte marker gene, as a cold-responsive protein of brown adipose tissue. We hypothesised a mechanistic relationship between cytochrome c oxidase activity and Cox7a1 protein levels affecting the oxidative capacity of brown adipose tissue and thus non-shivering thermogenesis. We subjected wildtype and Cox7a1 knockout mice to different temperature regimens and tested characteristics of brown adipose tissue activation. Cytochrome c oxidase activity, uncoupling protein 1 expression and maximal norepinephrine-induced heat production were gradually increased during cold-acclimation, but unaffected by Cox7a1 knockout. Moreover, the abundance of uncoupling protein 1 competent brite cells in white adipose tissue was not influenced by presence or absence of Cox7a1. Skin temperature in the interscapular region of neonates was lower in uncoupling protein 1 knockout pups employed as a positive control, but not in Cox7a1 knockout pups. Body mass gain and glucose tolerance did not differ between wildtype and Cox7a1 knockout mice fed with high fat or control diet. We conclude that brown adipose tissue function in mice does not require the presence of Cox7a1.
- Published
- 2015
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46. Cox4i2, Ifit2, and Prdm11 Mutant Mice: Effective Selection of Genes Predisposing to an Altered Airway Inflammatory Response from a Large Compendium of Mutant Mouse Lines.
- Author
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Horsch M, Aguilar-Pimentel JA, Bönisch C, Côme C, Kolster-Fog C, Jensen KT, Lund AH, Lee I, Grossman LI, Sinkler C, Hüttemann M, Bohn E, Fuchs H, Ollert M, Gailus-Durner V, de Angelis MH, and Beckers J
- Subjects
- Animals, Apoptosis Regulatory Proteins, Bronchoalveolar Lavage Fluid cytology, Bronchoalveolar Lavage Fluid immunology, Cytokines blood, Cytokines metabolism, Disease Models, Animal, Female, Gene Expression Profiling, Genetic Predisposition to Disease, Immunoglobulin E blood, Immunoglobulin E immunology, Immunoglobulins blood, Immunoglobulins immunology, Inflammation genetics, Inflammation immunology, Lymphocyte Activation immunology, Mice, Molecular Sequence Annotation, Ovalbumin immunology, RNA-Binding Proteins, Respiratory Tract Diseases genetics, Respiratory Tract Diseases immunology, Selection, Genetic, Transcription Factors, Transcriptome, Carrier Proteins genetics, Mutation, Proteins genetics
- Abstract
We established a selection strategy to identify new models for an altered airway inflammatory response from a large compendium of mutant mouse lines that were systemically phenotyped in the German Mouse Clinic (GMC). As selection criteria we included published gene functional data, as well as immunological and transcriptome data from GMC phenotyping screens under standard conditions. Applying these criteria we identified a few from several hundred mutant mouse lines and further characterized the Cox4i2tm1Hutt, Ifit2tm1.1Ebsb, and Prdm11tm1.1ahl lines following ovalbumin (OVA) sensitization and repeated OVA airway challenge. Challenged Prdm11tm1.1ahl mice exhibited changes in B cell counts, CD4+ T cell counts, and in the number of neutrophils in bronchoalveolar lavages, whereas challenged Ifit2tm1.1Ebsb mice displayed alterations in plasma IgE, IgG1, IgG3, and IgM levels compared to the challenged wild type littermates. In contrast, challenged Cox4i2tm1Hutt mutant mice did not show alterations in the humoral or cellular immune response compared to challenged wild type mice. Transcriptome analyses from lungs of the challenged mutant mouse lines showed extensive changes in gene expression in Prdm11tm1.1ahl mice. Functional annotations of regulated genes of all three mutant mouse lines were primarily related to inflammation and airway smooth muscle (ASM) remodeling. We were thus able to define an effective selection strategy to identify new candidate genes for the predisposition to an altered airway inflammatory response under OVA challenge conditions. Similar selection strategies may be used for the analysis of additional genotype-envirotype interactions for other diseases.
- Published
- 2015
- Full Text
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47. Autoantibodies in breast cancer sera are not epiphenomena and may participate in carcinogenesis.
- Author
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Madrid FF, Maroun MC, Olivero OA, Long M, Stark A, Grossman LI, Binder W, Dong J, Burke M, Nathanson SD, Zarbo R, Chitale D, Zeballos-Chávez R, and Peebles C
- Subjects
- Adult, Aged, Aged, 80 and over, Antigens, Nuclear, Breast Diseases immunology, Cell Nucleolus immunology, Centromere immunology, Centromere Protein B immunology, Centrosome immunology, Female, Humans, Middle Aged, Mitochondria immunology, Antibodies, Antinuclear blood, Breast Neoplasms immunology, Carcinogenesis immunology, Carcinoma in Situ immunology, Carcinoma, Ductal, Breast immunology, Immunoglobulin G blood
- Abstract
Background: The objective of this work was to demonstrate that autoantibodies in breast cancer sera are not epiphenomena, and exhibit unique immunologic features resembling the rheumatic autoimmune diseases., Methods: We performed a comprehensive study of autoantibodies on a collection of sera from women with breast cancer or benign breast disease, undergoing annual screening mammography. All women in this study had suspicious mammography assessment and underwent a breast biopsy. We used indirect immunofluorescence, the crithidia assay for anti-dsDNA antibodies, and multiple ELISAs for extractable nuclear antigens., Results: Autoantibodies were detected in virtually all patients with breast cancer, predominantly of the IgG1 and IgG3 isotypes. The profile detected in breast cancer sera showed distinctive features, such as antibodies targeting mitochondria, centrosomes, centromeres, nucleoli, cytoskeleton, and multiple nuclear dots. The majority of sera showing anti-mitochondrial antibodies did not react with the M2 component of pyruvate dehydrogenase, characteristic of primary biliary cirrhosis. Anti-centromere antibodies were mainly anti-CENP-B. ELISAs for extractable nuclear antigens and the assays for dsDNA were negative., Conclusions: The distinctive autoantibody profile detected in BC sera is the expression of tumor immunogenicity. Although some of these features resemble those in the rheumatic autoimmune diseases and primary biliary cirrhosis, the data suggest the involvement of an entirely different set of epithelial antigens in breast cancer. High titer autoantibodies targeting centrosomes, centromeres, and mitochondria were detected in a small group of healthy women with suspicious mammography assessment and no cancer by biopsy; this suggests that the process triggering autoantibody formation starts in the pre-malignant phase and that future studies using validated autoantibody panels may allow detection of breast cancer risk in asymptomatic women. Autoantibodies developing in breast cancer are not epiphenomena, but likely reflect an antigen-driven autoimmune response triggered by epitopes developing in the mammary gland during breast carcinogenesis. Our results support the validity of the multiple studies reporting association of autoantibodies with breast cancer. Results further suggest significant promise for the development of panels of breast cancer-specific, premalignant-phase autoantibodies, as well as studies on the autoantibody response to tumor associated antigens in the pathogenesis of cancer.
- Published
- 2015
- Full Text
- View/download PDF
48. MNRR1 (formerly CHCHD2) is a bi-organellar regulator of mitochondrial metabolism.
- Author
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Aras S, Bai M, Lee I, Springett R, Hüttemann M, and Grossman LI
- Subjects
- DNA-Binding Proteins, Electron Transport Complex IV metabolism, Gene Expression Regulation, Humans, Protein Binding, Stress, Physiological, Cell Nucleus chemistry, Mitochondria chemistry, Mitochondrial Proteins analysis, Transcription Factors analysis
- Abstract
Our understanding of stress-associated regulatory mechanisms for mitochondria remains incomplete. We now report a new regulator of mitochondrial metabolism, the coiled-coil-helix-coiled-coil-helix domain-containing protein 2 (CHCHD2) which, based on the functionality described here, is renamed MNRR1 (Mitochondria Nuclear Retrograde Regulator 1). It functions in a novel way by acting in two cellular compartments, mitochondria and nucleus. In normally growing cells most MNRR1 is located in mitochondria; during stress most MNRR1 is now located in the nucleus. MNRR1 is imported to the mitochondrial intermembrane space by a Mia40-mediated pathway, where it binds to cytochrome c oxidase (COX). This association is required for full COX activity. Decreased MNRR1 levels produce widespread dysfunction including reduced COX activity, membrane potential, and growth rate, and increased reactive oxygen species and mitochondrial fragmentation. In the nucleus, MNRR1 acts as a transcription factor, one of whose targets is the COX subunit 4 isoform, COX4I2, which is transcriptionally stimulated by hypoxia. This MNRR1-mediated stress response may provide an important survival mechanism for cells under conditions of oxidative or hypoxic stress, both in the acute phase by altering mitochondrial oxygen utilization and in the chronic phase by promoting COX remodeling., (Copyright © 2014 © Elsevier B.V. and Mitochondria Research Society. Published by Elsevier B.V. All rights reserved.)
- Published
- 2015
- Full Text
- View/download PDF
49. Reply to Skoyles: Decline in growth rate, not muscle mass, predicts the human childhood peak in brain metabolism.
- Author
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Kuzawa CW, Chugani HT, Grossman LI, Lipovich L, Muzik O, Hof PR, Wildman DE, Sherwood CC, Leonard WR, and Lange N
- Subjects
- Female, Humans, Male, Basal Metabolism, Biological Evolution, Brain embryology, Brain metabolism
- Published
- 2014
- Full Text
- View/download PDF
50. Metabolic costs and evolutionary implications of human brain development.
- Author
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Kuzawa CW, Chugani HT, Grossman LI, Lipovich L, Muzik O, Hof PR, Wildman DE, Sherwood CC, Leonard WR, and Lange N
- Subjects
- Adult, Aging metabolism, Body Weight, Female, Glucose metabolism, Humans, Male, Young Adult, Basal Metabolism, Biological Evolution, Brain embryology, Brain metabolism
- Abstract
The high energetic costs of human brain development have been hypothesized to explain distinctive human traits, including exceptionally slow and protracted preadult growth. Although widely assumed to constrain life-history evolution, the metabolic requirements of the growing human brain are unknown. We combined previously collected PET and MRI data to calculate the human brain's glucose use from birth to adulthood, which we compare with body growth rate. We evaluate the strength of brain-body metabolic trade-offs using the ratios of brain glucose uptake to the body's resting metabolic rate (RMR) and daily energy requirements (DER) expressed in glucose-gram equivalents (glucosermr% and glucoseder%). We find that glucosermr% and glucoseder% do not peak at birth (52.5% and 59.8% of RMR, or 35.4% and 38.7% of DER, for males and females, respectively), when relative brain size is largest, but rather in childhood (66.3% and 65.0% of RMR and 43.3% and 43.8% of DER). Body-weight growth (dw/dt) and both glucosermr% and glucoseder% are strongly, inversely related: soon after birth, increases in brain glucose demand are accompanied by proportionate decreases in dw/dt. Ages of peak brain glucose demand and lowest dw/dt co-occur and subsequent developmental declines in brain metabolism are matched by proportionate increases in dw/dt until puberty. The finding that human brain glucose demands peak during childhood, and evidence that brain metabolism and body growth rate covary inversely across development, support the hypothesis that the high costs of human brain development require compensatory slowing of body growth rate.
- Published
- 2014
- Full Text
- View/download PDF
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