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Macrophages restrain microbial infection and reinstate tissue homeostasis. The mitochondria govern macrophage metabolism and serve as pivot in innate immunity, thus acting as immunometabolic regulon. Metabolic pathways produce electron flows that end up in mitochondrial electron transport chain (mtETC), made of super-complexes regulating multitude of molecular and biochemical processes. Cell-intrinsic and extrinsic factors influence mtETC structure and function, impacting several aspects of macrophage immunity. These factors provide the macrophages with alternate fuel sources and metabolites, critical to gain functional competence and overcoming pathogenic stress. Mitochondrial reactive oxygen species (mtROS) and oxidative phosphorylation (OXPHOS) generated through the mtETC are important innate immune attributes, which help macrophages in mounting antibacterial responses. Recent studies have demonstrated the role of mtETC in governing mitochondrial dynamics and macrophage polarization (M1/M2). M1 macrophages are important for containing bacterial pathogens and M2 macrophages promote tissue repair and wound healing. Thus, mitochondrial bioenergetics and metabolism are intimately coupled with innate immunity. In this review, we have addressed mtETC function as innate rheostats that regulate macrophage reprogramming and innate immune responses. Advancement in this field encourages further exploration and provides potential novel macrophage-based therapeutic targets to control unsolicited inflammation.

Aim: We investigate the mechanism whereby chlorpyrifos (CHI), an environmental toxin, causes liver injury by inducing ferroptosis in hepatocytes. Methods: The toxic dose (LD50 = 50 μM) of CHI for inducing AML12 injury in normal mouse hepatocytes was determined, and the ferroptosis-related indices were measured, including the levels of SOD, MDA and GSH-Px, as well as the cellular content of iron ions. JC-1 and DCFH-DA assays were employed to detect the mtROS levels, the levels of mitochondrial proteins (GSDMD, NT-GSDMD), as well as the cellular levels of ferroptosis-related proteins (P53, GPX4, MDM2, SLC7A11). We knocked out the GSDMD and P53 in AML12 and observed the CHI-induced ferroptosis of ALM12 after applying YGC063, an ROS inhibitor. In animal experiments, we explored the effect of CHI on liver injury by using conditional GSDMD-knockout mice (C57BL/6 N-GSDMDem1(flox)Cya) and ferroptosis inhibitor Fer-1. Small molecule-protein docking and Pull-down assay were employed to verify the association between CHI and GSDMD. Results: We found that CHI could induce ferroptosis of AML12. CHI promoted the cleavage of GSDMD, leading to upregulation of mitochondrial NT-GSDMD expression, as well as ROS levels. P53 activation promoted the ferroptosis. Knock out of GSDMD and P53 could inhibit the CHI-induced ferroptosis, and YGC063 could also inhibit ferroptosis. In mice experiments, GSDMD knockout or Fer-1 intervention could significantly inhibit the CHI-induced liver injury. CHI promoted the cleavage of GSDMD by binding to its SER234 site. Conclusion: CHI can bind to GSDMD to promote its cleavage, while NT-GSDMD can open mitochondrial membrane to promote the mtROS release. Cytoplasmic upregulation of ROS levels can facilitate the P53-mediated ferroptosis. GSDMD-mtROS is the primary mechanism whereby CHI induces ferroptosis in hepatocytes.

Diapause is a long-lived stage which has evolved into an important strategy for insects to circumvent extreme environments. In the pupal stage, Helicoverpa armigera can enter diapause, a state characterized by significantly decreased metabolic activity and enhanced stress resistance, to survive cold winters. Previous studies have shown that reactive oxygen species (ROS) can promote the diapause process by regulating a distinct insulin signaling pathway. However, the source of ROS in the diapause-destined pupal brains and mechanisms by which ROS regulate diapause are still unknown. In this study, we showed that diapause-destined pupal brains accumulated high levels of mitochondrial ROS (mtROS) and total ROS during the diapause process, suggesting that mitochondria are the main source of ROS in diapause-destined pupal brains. In addition, injection of 2-deoxy-D-glucose (DOG), a glucose metabolism inhibitor, could delay pupal development by elevating mtROS levels in the nondiapause-destined pupal brains. Furthermore, the injection of a metabolite mixture to increase metabolic activity could avert the diapause process in diapause-destined pupae by decreasing mtROS levels. We also found that ROS could activate HSP60 expression and promote the stability of the HSP60-Lon complex, increasing its ability to degrade mitochondrial transcription factor A (TFAM) and decreasing mitochondrial activity or biogenesis under oxidative stress. Thus, this study illustrated the beneficial function of ROS in diapause or lifespan extension by decreasing mitochondrial activity.

Mitophagy is a distinct physiological process that can have beneficial or deleterious effects in particular tissues. Prior research suggests that mitophagic activity can be triggered by CaO2-PM-CsPbBr3 QDs, yet the specific role that mitophagy plays in hepatic injury induced by CaO2-PM-CsPbBr3 QDs has yet to be established. Accordingly, in this study a series of mouse model- and cell-based experiments were performed that revealed the ability of CaO2-PM-CsPbBr3 QDs to activate mitophagic activity. Golm1 was upregulated in response to CaO2-PM-CsPbBr3 QDs treatment, and overexpressing Golm1 induced autophagic flux in the murine liver and hepatocytes, whereas knocking down Golm1 had the opposite effect. CaO2-PM-CsPbBr3 QDs were also able to Golm1 expression, in turn promoting the degradation of P53 and decreasing the half-life of this protein. Overexpressing Golm1 was sufficient to suppress the apoptotic death of hepatocytes in vitro and in vivo, whereas the knockdown of Golm1 had the opposite effect. The ability of Golm1 to promote p53-mediated autophagy was found to be associated with the disruption of Beclin-1 binding to Bcl-2, and the Golm1 N-terminal domain was determined to be required for p53 interactions, inducing autophagic activity in a manner independent of helicase activity or RNA binding. Together, these results indicate that inhibiting Golm1 can promote p53-dependent autophagy via disrupting Beclin-1 binding to Bcl-2, highlighting a novel approach to mitigating liver injury induced by CaO2-PM-CsPbBr3 QDs., 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 B.V. All rights reserved.)

YAP1 and TAZ are transcriptional co-activator proteins that play fundamental roles in many biological processes, from cell proliferation and cell lineage fate determination to tumorigenesis. We previously demonstrated that Limb Expression 1 (LIX1) regulates YAP1 and TAZ activity and controls digestive mesenchymal progenitor proliferation. However, LIX1 mode of action remains elusive. Here, we found that endogenous LIX1 is localized in mitochondria and is anchored to the outer mitochondrial membrane through S-palmitoylation of cysteine 84, a residue conserved in all LIX1 orthologs. LIX1 downregulation altered the mitochondrial ultrastructure, resulting in a significantly decreased respiration and attenuated production of mitochondrial reactive oxygen species (mtROS). Mechanistically, LIX1 knock-down impaired the stability of the mitochondrial proteins PHB2 and OPA1 that are found in complexes with mitochondrial-specific phospholipids and are required for cristae organization. Supplementation with unsaturated fatty acids counteracted the effects of LIX1 knock-down on mitochondrial morphology and ultrastructure and restored YAP1/TAZ signaling. Collectively, our data demonstrate that LIX1 is a key regulator of cristae organization, modulating mtROS level and subsequently regulating the signaling cascades that control fate commitment of digestive mesenchyme-derived cells.

The goal of this study was to analyze whether mitochondria-associated endoplasmic reticulum membrane (MAMs) dysfunction mediated arsenic (As)-evoked pulmonary ferroptosis and acute lung injury (ALI). As exposure led to alveolar structure damage, inflammatory cell infiltration and pulmonary function decline in mice. Ferritin, the marker of iron overload, was increased, GPX4, the index of lipid peroxidation, was decreased in As-exposed lungs and pulmonary epithelial cells (MLE-12). Pretreatment with ferrostatin-1 (Fer-1), the inhibitor of ferroptosis, alleviated As-evoked ALI. In addition, As-induced non-heme iron deposition was inhibited in Fer-1 pretreated-mice. Moreover, As-triggered mitochondria damage and ferroptosis were mitigated in Fer-1 pretreated-MLE-12 cells. Mechanistically, PERK phosphorylation and mitofusin-2 (Mfn-2) reduction was observed in As-exposed MLE-12 cells and mice lungs. Additionally, the interaction between PERK and Mfn-2 was downregulated and MAMs dysfunction was observed in As-exposed MLE-12 cells. Intriguingly, PERK inhibitor and Mfn-2-overexpression all mitigated As-induced ferroptosis in MLE-12 cells. Additionally, CLPP and mtHSP70, the markers of mitochondrial stress, were upregulated, mitochondrial ROS (mtROS) was elevated, mitochondrial membrane potential (MMP) and ATP were decreased in As-exposed MLE-12 cells. Mitoquinone mesylate (MitoQ), a novel mitochondrial-targeted antioxidant, alleviated As-induced excess mtROS, mitochondrial stress, MAMs dysfunction in pulmonary epithelial cells. Similarly, in vivo experiments indicated that MitoQ pretreatment countered As-induced pulmonary ferroptosis and ALI. These data indicated that mtROS-initiated MAMs dysfunction is, at least partially, implicated in As-evoked ferroptosis and ALI.

As essential regulators of mitochondrial quality control, mitochondrial dynamics and mitophagy play key roles in maintenance of metabolic health and cellular homeostasis. Here we show that knockdown of the membrane-inserted scaffolding and structural protein caveolin-1 (Cav-1) and expression of tyrosine 14 phospho-defective Cav-1 mutant (Y14F), as opposed to phospho-mimicking Y14D, altered mitochondrial morphology, and increased mitochondrial matrix mixing, mitochondrial fusion and fission dynamics as well as mitophagy in MDA-MB-231 triple negative breast cancer cells. Further, we found that interaction of Cav-1 with mitochondrial fusion/fission machinery Mitofusin 2 (Mfn2) and Dynamin related protein 1 (Drp1) was enhanced by Y14D mutant indicating Cav-1 Y14 phosphorylation prevented Mfn2 and Drp1 translocation to mitochondria. Moreover, limiting mitochondrial recruitment of Mfn2 diminished formation of the PINK1/Mfn2/Parkin complex required for initiation of mitophagy resulting in accumulation of damaged mitochondria and ROS (mtROS). Thus, these studies indicate that phospho-Cav-1 may be an important switch mechanism in cancer cell survival which could lead to novel strategies for complementing cancer therapies.

Tumor suppressor p53 plays a pivotal role in orchestrating mitochondrial remodeling by regulating their content, fusion/fission processes, and intracellular signaling molecules that are associated with mitophagy and apoptosis pathways. In order to determine a molecular mechanism underlying flow-mediated mitochondrial remodeling in endothelial cells, we examined, herein, the role of p53 on mitochondrial adaptations to physiological flow and its relevance to vascular function using endothelial cell-specific p53 deficient mice. We observed no changes in aerobic capacity, basal blood pressure, or endothelial mitochondrial phenotypes in the endothelial p53 mull animals. However, after 7 weeks of voluntary wheel running exercise, blood pressure reduction and endothelial mitochondrial remodeling (biogenesis, elongation, and mtDNA replication) were substantially blunted in endothelial p53 null animals compared to the wild-type, subjected to angiotensin II-induced hypertension. In addition, endothelial mtDNA lesions were significantly reduced following voluntary running exercise in wild-type mice, but not in the endothelial p53 null mice. Moreover, in vitro studies demonstrated that unidirectional laminar flow exposure significantly increased key putative regulators for mitochondrial remodeling and reduced mitochondrial reactive oxygen species generation and mtDNA damage in a p53-dependent manner. Mechanistically, unidirectional laminar flow instigated translocalization of p53 into the mitochondrial matrix where it binds to mitochondrial transcription factor A, TFAM, resulting in improving mtDNA integrity. Taken together, our findings suggest that p53 plays an integral role in mitochondrial remodeling under physiological flow condition and the flow-induced p53-TFAM axis may be a novel molecular intersection for enhancing mitochondrial homeostasis in endothelial cells.

Ferroptosis is a newly recognized type of programmed cell death that is implicated in the pathophysiological process of neurological disorders. Our previous studies have revealed that exposure to high concentrations of fluoride for long periods of time induces hippocampal neural injury and cognitive deficits. However, whether ferroptosis is involved in fluoride-induced neuronal death and the underlying mechanism remain unknown. In this study, the results indicated that exposure to high fluoride triggered ferroptosis in SH-SY5Y cells and in the hippocampus of mice. Fluoride exposure accelerated the lysosomal degradation of GPX4 and led to neuronal ferroptosis, while GPX4 overexpression protected SH-SY5Y cells against fluoride-induced neurotoxicity. Intriguingly, the enhanced chaperone-mediated autophagy (CMA) induced by fluoride stimulation was responsible for GPX4 degradation because the inhibition of CMA activity by LAMP2A knockdown effectively prevented fluoride-induced GPX4 loss. Furthermore, mitochondrial ROS (mtROS) accumulation caused by fluoride contributed to CMA activation-mediated GPX4 degradation and subsequent neuronal ferroptosis. Notably, the ferroptosis-specific inhibitor ferrostatin-1 (Fer-1) or the ROS scavenger N-acetyl-L-cysteine (NAC) alleviated fluoride-evoked hippocampal neuronal death and synaptic injury as well as cognitive deficits in mice. The present studies indicates that ferroptosis is a novel mechanism of fluoride-induced neurotoxicity and that chronic fluoride exposure facilitates GPX4 degradation via mtROS chaperone-mediated autophagy, leading to neuronal ferroptosis and cognitive impairment., 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. Graphical abstract created with Biorender.com., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Activated microglia are an important type of innate immune cell in the brain, and they secrete inflammatory cytokines into the extracellular milieu, exert neurotoxicity to surrounding neurons and are involved in the pathogenesis of many brain disorders. Quercetin (Qu), a natural flavonoid, is known to have anti-inflammatory and antioxidant properties. Previous studies have shown that both increased reactive oxygen species (ROS) stress and decreased autophagy participate in the activation of microglial. In the current study, we showed that Qu significantly attenuated LPS-induced inflammatory factor production, cell proliferation and NF-κB activation of microglia. Importantly, Qu decreased the levels of NLR family, pyrin domain containing three (NLRP3) inflammasome and pyroptosis-related proteins, including NLRP3, active caspase-1, GSDMD N-terminus and cleaved IL-1β. Further study indicated that this anti-inflammatory effect of Qu was associated with mitophagy regulation. Importantly, Qu promoted mitophagy to enhance damaged mitochondrial elimination, which then reduced mtROS accumulation and alleviated NLRP3 inflammasome activation. Then, we confirmed that Qu treatment protected primary neurons against LPS-induced microglial toxicity and alleviated neurodegeneration in both depression and PD mouse models. Further IL-1β administration blunted these neuroprotective effects of Qu in vitro and in vivo. This work illustrated that Qu prevents neuronal injury via inhibition of mtROS-mediated NLRP3 inflammasome activation in microglia through promoting mitophagy, which provides a potential novel therapeutic strategy for neuroinflammation-related diseases.

Copper (Cu) is a trace element necessary in animals as well as human beings. However, excessive Cu is toxic to immunocytes, but the precise mechanism is largely unclear so far. This work was conducted aiming to examine the Cu-mediated autophagy mechanism together with its role in Cu toxicology in RAW264.7 cells. Here, we demonstrated that CuSO4 reduced the cell viability depending on its dose. CuSO4 could obviously increase autophagy in RAW264.7 cells. According to the obtained results, CuSO4 induced autophagy through Akt/AMPK/mTOR pathway which characterized by down regulation of p-Akt (Ser473)/Akt, p-mTOR/mTOR, p-ULK1(Ser757)/ULK1 and subsequent up-regulation of p-AMPKα/AMPKα and p-ULK1(Ser555)/ULK1. Furthermore, CuSO4 significantly induced the production of mitochondrial reactive oxygen species (mtROS). In addition, CuSO4-mediated apoptosis and autophagy might be suppressed through suppressing mtROS generation by exposure to Mito-TEMPO. Intriguingly, autophagy promotion with rapamycin could decrease the apoptosis and the inhibition of autophagy with knock down Atg5 could enhance the apoptosis induced by CuSO4. Moreover, our results suggested that mtROS is the original cause in CuSO4-induced apoptosis and autophagy. Additionally, CuSO4 induced autophagy through mtROS-dependent Akt/AMPK/mTOR signalling pathwayin RAW264.7 cells. Moreover, autophagy activation might potentially generate a protection mechanism for improving CuSO4-induced RAW264.7 cell apoptosis.

Lead (Pb), a well-known environmental pollutant, could cause damage of microglia, the resident macrophages vitally regulating inflammation in brain. Previous studies have found that Pb exposure induces typical pro-inflammatory factors release, such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), but what effects of Pb treatment below the dose causing these factors release are unknown. Thus, cytokines assay was performed to identify the factors released from Pb-treated BV-2 cells at 2.5 μM, causing no effects on TNF-α, IL-1β, and IL-6 release and cell death. Cytokines assay identified low doses of Pb exposure mainly induce an increase in specific chemokines, including CXCL10, CCL2, and CXCL2, which were confirmed by ELISA. Subsequent assessment found Pb could damage mitochondria function and generate mitochondrial reactive oxygen species (mtROS), and Mito TEMPO, a specific inhibitor of mtROS, suppressed Pb-caused upregulation of CXCL10 and CCL2, but not CXCL2. Finally, we determined that mtROS mediated Pb-induced activation of NF-κB pathway, as Mito TEMPO treatment inhibited P-p65/p65 escalation during Pb treatment. Inhibition of NF-κB pathway by Bay11-7821 suppressed the release of CXCL10 and CCL2. Collectively, low dose of Pb induces the release of CXCL10 and CCL2 chemokines, but not TNF-α and IL-1β, via mtROS/NF-κB activation in BV-2 cells., 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 Elsevier B.V. All rights reserved.)

Aim: We investigate the mechanism whereby chlorpyrifos (CHI), an environmental toxin, causes liver injury by inducing ferroptosis in hepatocytes., Methods: The toxic dose (LD50 = 50 μM) of CHI for inducing AML12 injury in normal mouse hepatocytes was determined, and the ferroptosis-related indices were measured, including the levels of SOD, MDA and GSH-Px, as well as the cellular content of iron ions. JC-1 and DCFH-DA assays were employed to detect the mtROS levels, the levels of mitochondrial proteins (GSDMD, NT-GSDMD), as well as the cellular levels of ferroptosis-related proteins (P53, GPX4, MDM2, SLC7A11). We knocked out the GSDMD and P53 in AML12 and observed the CHI-induced ferroptosis of ALM12 after applying YGC063, an ROS inhibitor. In animal experiments, we explored the effect of CHI on liver injury by using conditional GSDMD-knockout mice (C57BL/6 N-GSDMD em1(flox)Cya ) and ferroptosis inhibitor Fer-1. Small molecule-protein docking and Pull-down assay were employed to verify the association between CHI and GSDMD., Results: We found that CHI could induce ferroptosis of AML12. CHI promoted the cleavage of GSDMD, leading to upregulation of mitochondrial NT-GSDMD expression, as well as ROS levels. P53 activation promoted the ferroptosis. Knock out of GSDMD and P53 could inhibit the CHI-induced ferroptosis, and YGC063 could also inhibit ferroptosis. In mice experiments, GSDMD knockout or Fer-1 intervention could significantly inhibit the CHI-induced liver injury. CHI promoted the cleavage of GSDMD by binding to its SER234 site., Conclusion: CHI can bind to GSDMD to promote its cleavage, while NT-GSDMD can open mitochondrial membrane to promote the mtROS release. Cytoplasmic upregulation of ROS levels can facilitate the P53-mediated ferroptosis. GSDMD-mtROS is the primary mechanism whereby CHI induces ferroptosis in hepatocytes., 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 The Authors. Published by Elsevier Inc. All rights reserved.)

Myocytes undergoing hypoxia condition can recruit macrophages and cause pro-inflammation initiation around the injury area. Mitochondrial dysfunction is related to macrophage pyroptosis. Stomatin-like protein-2 (SLP-2) can regulate mitochondrial biogenesis and function. Whether SLP-2 could affect macrophage pyroptosis remains unclear. In this study, bone marrow derived macrophages (BMDMs) were extracted from WT and SLP-2 knocked out mice, then stimulated by LPS/Nigericin. Western blot showed that SLP-2 -/- promoted the expression of NLRP3, GSDMD-N, caspase-11 in macrophages, which means the deficiency of SLP-2 augments macrophage pyroptosis. Higher fluorescence intensity of dihydroethidium and TUNEL represented the increased ROS releasing and macrophage programmed death in SLP-2 deficiency groups. The immunofluorescence intensity of MtioTracker Red decreased and that of mitochondrial ROS (mtROS) increased in SLP-2 deletion groups with LPS/Nigericin stimulation, representing the increased mitochondrial damage. The expression level of HIF-1α increased in SLP-2 deletion macrophages with LPS and Nigericin stimulation. The level of Parkin and the ratio of LC3II/I decreased in SLP-2 deficiency macrophages after stimulated by LPS/Nigericin, compared with untreated macrophages. H9c2 cells were cultured in hypoxia condition before being cocultured with macrophage supernatant. The cocultured H9c2 cells were injured due to the serious pyroptosis of SLP-2 deficiency macrophages. According to these results, we suggest that SLP-2 can reduce macrophage pyroptosis and relieve hypoxia H9c2 cells injury through protecting mitochondrial function., Competing Interests: Declaration of competing interest There is no conflict of interest regarding the publication of this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The goal of this study was to analyze whether mitochondria-associated endoplasmic reticulum membrane (MAMs) dysfunction mediated arsenic (As)-evoked pulmonary ferroptosis and acute lung injury (ALI). As exposure led to alveolar structure damage, inflammatory cell infiltration and pulmonary function decline in mice. Ferritin, the marker of iron overload, was increased, GPX4, the index of lipid peroxidation, was decreased in As-exposed lungs and pulmonary epithelial cells (MLE-12). Pretreatment with ferrostatin-1 (Fer-1), the inhibitor of ferroptosis, alleviated As-evoked ALI. In addition, As-induced non-heme iron deposition was inhibited in Fer-1 pretreated-mice. Moreover, As-triggered mitochondria damage and ferroptosis were mitigated in Fer-1 pretreated-MLE-12 cells. Mechanistically, PERK phosphorylation and mitofusin-2 (Mfn-2) reduction was observed in As-exposed MLE-12 cells and mice lungs. Additionally, the interaction between PERK and Mfn-2 was downregulated and MAMs dysfunction was observed in As-exposed MLE-12 cells. Intriguingly, PERK inhibitor and Mfn-2-overexpression all mitigated As-induced ferroptosis in MLE-12 cells. Additionally, CLPP and mtHSP70, the markers of mitochondrial stress, were upregulated, mitochondrial ROS (mtROS) was elevated, mitochondrial membrane potential (MMP) and ATP were decreased in As-exposed MLE-12 cells. Mitoquinone mesylate (MitoQ), a novel mitochondrial-targeted antioxidant, alleviated As-induced excess mtROS, mitochondrial stress, MAMs dysfunction in pulmonary epithelial cells. Similarly, in vivo experiments indicated that MitoQ pretreatment countered As-induced pulmonary ferroptosis and ALI. These data indicated that mtROS-initiated MAMs dysfunction is, at least partially, implicated in As-evoked ferroptosis and ALI., (Copyright © 2022. Published by Elsevier Inc.)

Somatic mutations in mitochondrial DNA may provide a new avenue for cancer therapy due to their associations to a number of cancers and a tendency of homoplasmicity. In consideration of mitochondrial features and its relatively small genome size, a nucleotide-based targeting approach is a considerably more promising option. To explore the efficacy of short linear N-methylpyrrole-N-methylimidazole polyamide (PI polyamide), we synthesized a five-ring short PI polyamide that provided sequence-specific homing for the A3243G mitochondrial mutation upon conjugation with triphenylphosphonium cation (TPP). This PI polyamide-TPP was able to induce cytotoxicity in HeLamtA3243G cybrid cells, while preserving preferential binding for oligonucleotides containing the A3243G motif from melting temperature assays. The PI polyamide-TPP also localized in the mitochondria in HeLamtA3243G cells and induced mitochondrial reactive oxygen species production, mitophagy and apoptosis in a mutation-specific fashion compared to the wild-type HeLamtHeLa cybrids; normal human dermal fibroblasts were also relatively unaffected to suggest discriminating selectivity for the mutant mitochondria, offering a novel outlook for cancer therapy via mitochondrial homing of short linear PIP-TPPs., 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 © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Hepatic insulin resistance (IR) is the key event for arsenic-caused type 2 diabetes (T2D). However, the unequivocal mechanism of arsenic-induced hepatic IR remains unclear. The current study determined the role of NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation in arsenic-induced IR and revealed the underlying mechanism. Three-month NaAsO 2 gavage led to glucose intolerance and insulin insensitivity, impaired hepatic insulin signaling. Additionally, NaAsO 2 upregulated the level of oxidized mitochondrial DNA (ox-mtDNA) and mitophagy, thereby activating the NLRP3 inflammasome in SD rat liver. In vitro, we demonstrated that NaAsO 2 -induced IR depended upon the NLRP3 inflammasome activation. Moreover, inhibiting mitophagy mitigated the NLRP3 inflammasome activation and impaired insulin signaling induced by NaAsO 2 . Furthermore, mitochondrial reactive oxygen species (mtROS) scavenger alleviated the upregulated ox-mtDNA and mitophagy, thereby inhibiting the NLRP3 inflammasome activation, and improving insulin signaling. Taken together, these data demonstrated that mtROS-triggered ox-mtDNA, mitophagy, and the activation of NLRP3 inflammasome was involved in arsenic-induced hepatic IR., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Chronic arsenic exposure is a significantly risk factor for pancreatic dysfunction and type 2 diabetes (T2D). Ferroptosis is a newly identified iron-dependent form of oxidative cell death that relies on lipid peroxidation. Previous data have indicated that ferroptosis is involved in various diseases, including cancers, neurodegenerative diseases, and T2D. However, the concrete effect and mechanism of ferroptosis on pancreatic dysfunction triggered by arsenic remains unknown. In this study, we verified that ferroptosis occurred in animal models of arsenic-induced pancreatic dysfunction through assessing proferroptotic markers and morphological changes in mitochondria. In vitro, arsenic caused execution of ferroptosis in a dose-dependent manner, which could be significantly reduced by ferrostatin-1. Additionally, arsenic damaged mitochondria manifested as diminishing of mitochondrial membrane potential, reduced cytochrome c level and production of mitochondrial reactive oxygen species (MtROS) in MIN6 cells. Using the Mito-TEMPO, we found the autophagy level and subsequent ferroptotic cell death induced by arsenic were both alleviated. With autophagy inhibitor chloroquine, we further revealed that ferritin regulated ferroptosis through the MtROS-autophagy pathway. Collectively, NaAsO 2 -induced ferroptotic cell death is relied on the MtROS-dependent autophagy by regulating the iron homeostasis. Ferroptosis is involved in pancreatic dysfunction triggered by arsenic, and arsenic-induced ferroptosis involves MtROS, autophagy, ferritin., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Diabetes-related vascular complication rates remain unacceptably high despite guideline-based medical therapies that are significantly more effective in individuals without diabetes. This critical gap represents an opportunity for researchers and clinicians to collaborate on targeting mechanisms and pathways that specifically contribute to vascular pathology in patients with diabetes mellitus. Dysfunctional mitochondria producing excessive mitochondrial reactive oxygen species (mtROS) play a proximal cell-signaling role in the development of vascular endothelial dysfunction in the setting of diabetes. Targeting the mechanisms of production of mtROS or mtROS themselves represents an attractive method to reduce the prevalence and severity of diabetic vascular disease. This review focuses on the role of mitochondria in the development of diabetic vascular disease and current developments in methods to improve mitochondrial health to improve vascular outcomes in patients with DM., (Copyright © 2018. Published by Elsevier Inc.)