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507 results on '"McCaffery, J. Michael"'

2. Defining functional classes of Barth syndrome mutation in humans

Author

Lu, Ya-Wen, Galbraith, Laura, Herndon, Jenny D, Lu, Ya-Lin, Pras-Raves, Mia, Vervaart, Martin, Van Kampen, Antoine, Luyf, Angela, Koehler, Carla M, McCaffery, J Michael, Gottlieb, Eyal, Vaz, Frederic M, and Claypool, Steven M

Subjects
Genetics, Pediatric, Congenital Structural Anomalies, Biotechnology, Aetiology, 2.1 Biological and endogenous factors, Acyltransferases, Animals, Barth Syndrome, Cells, Cultured, Fibroblasts, HEK293 Cells, Humans, Mice, Mitochondria, Heart, Mitochondria, Liver, Mutation, Protein Isoforms, Skin, Transcription Factors, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

The X-linked disease Barth syndrome (BTHS) is caused by mutations in TAZ; TAZ is the main determinant of the final acyl chain composition of the mitochondrial-specific phospholipid, cardiolipin. To date, a detailed characterization of endogenous TAZ has only been performed in yeast. Further, why a given BTHS-associated missense mutation impairs TAZ function has only been determined in a yeast model of this human disease. Presently, the detailed characterization of yeast tafazzin harboring individual BTHS mutations at evolutionarily conserved residues has identified seven distinct loss-of-function mechanisms caused by patient-associated missense alleles. However, whether the biochemical consequences associated with individual mutations also occur in the context of human TAZ in a validated mammalian model has not been demonstrated. Here, utilizing newly established monoclonal antibodies capable of detecting endogenous TAZ, we demonstrate that mammalian TAZ, like its yeast counterpart, is localized to the mitochondrion where it adopts an extremely protease-resistant fold, associates non-integrally with intermembrane space-facing membranes and assembles in a range of complexes. Even though multiple isoforms are expressed at the mRNA level, only a single polypeptide that co-migrates with the human isoform lacking exon 5 is expressed in human skin fibroblasts, HEK293 cells, and murine heart and liver mitochondria. Finally, using a new genome-edited mammalian BTHS cell culture model, we demonstrate that the loss-of-function mechanisms for two BTHS alleles that represent two of the seven functional classes of BTHS mutation as originally defined in yeast, are the same when modeled in human TAZ.

Published
2016

3. Mitochondrial Transfer by Photothermal Nanoblade Restores Metabolite Profile in Mammalian Cells

Author

Wu, Ting-Hsiang, Sagullo, Enrico, Case, Dana, Zheng, Xin, Li, Yanjing, Hong, Jason S, TeSlaa, Tara, Patananan, Alexander N, McCaffery, J Michael, Niazi, Kayvan, Braas, Daniel, Koehler, Carla M, Graeber, Thomas G, Chiou, Pei-Yu, and Teitell, Michael A

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Genetics, Biological Sciences, Biotechnology, 2.1 Biological and endogenous factors, 1.1 Normal biological development and functioning, Animals, Base Sequence, Cell Line, Tumor, Clone Cells, DNA, Mitochondrial, Energy Metabolism, Gene Expression Regulation, Humans, Light, Mammals, Metabolome, Metabolomics, Mitochondria, Nanoparticles, Reproducibility of Results, Temperature, Medical Biochemistry and Metabolomics, Endocrinology & Metabolism, Biochemistry and cell biology, Medical biochemistry and metabolomics
Abstract

mtDNA sequence alterations are challenging to generate but desirable for basic studies and potential correction of mtDNA diseases. Here, we report a new method for transferring isolated mitochondria into somatic mammalian cells using a photothermal nanoblade, which bypasses endocytosis and cell fusion. The nanoblade rescued the pyrimidine auxotroph phenotype and respiration of ρ0 cells that lack mtDNA. Three stable isogenic nanoblade-rescued clones grown in uridine-free medium showed distinct bioenergetics profiles. Rescue lines 1 and 3 reestablished nucleus-encoded anapleurotic and catapleurotic enzyme gene expression patterns and had metabolite profiles similar to the parent cells from which the ρ0 recipient cells were derived. By contrast, rescue line 2 retained a ρ0 cell metabolic phenotype despite growth in uridine-free selection. The known influence of metabolite levels on cellular processes, including epigenome modifications and gene expression, suggests metabolite profiling can help assess the quality and function of mtDNA-modified cells.

Published
2016

4. UCP2 regulates energy metabolism and differentiation potential of human pluripotent stem cells

Author

Zhang, Jin, Khvorostov, Ivan, Hong, Jason S, Oktay, Yavuz, Vergnes, Laurent, Nuebel, Esther, Wahjudi, Paulin N, Setoguchi, Kiyoko, Wang, Geng, Do, Anna, Jung, Hea-Jin, McCaffery, J Michael, Kurland, Irwin J, Reue, Karen, Lee, Wai-Nang P, Koehler, Carla M, and Teitell, Michael A

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Information and Computing Sciences, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
Abstract

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Published
2016

5. Titration of mitochondrial fusion rescues Mff-deficient cardiomyopathy

Author

Chen, Hsiuchen, Ren, Shuxun, Clish, Clary, Jain, Mohit, Mootha, Vamsi, McCaffery, J Michael, and Chan, David C

Subjects
Biochemistry and Cell Biology, Biological Sciences, Cardiovascular, Heart Disease, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, Animals, Cardiomyopathy, Dilated, Cells, Cultured, Female, Genetic Pleiotropy, Male, Membrane Proteins, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Knockout, Mitochondria, Heart, Mitochondrial Dynamics, Mitochondrial Proteins, Titrimetry, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
Abstract

Defects in mitochondrial fusion or fission are associated with many pathologies, raising the hope that pharmacological manipulation of mitochondrial dynamics may have therapeutic benefit. This approach assumes that organ physiology can be restored by rebalancing mitochondrial dynamics, but this concept remains to be validated. We addressed this issue by analyzing mice deficient in Mff, a protein important for mitochondrial fission. Mff mutant mice die at 13 wk as a result of severe dilated cardiomyopathy leading to heart failure. Mutant tissue showed reduced mitochondrial density and respiratory chain activity along with increased mitophagy. Remarkably, concomitant deletion of the mitochondrial fusion gene Mfn1 completely rescued heart dysfunction, life span, and respiratory chain function. Our results show for the first time that retuning the balance of mitochondrial fusion and fission can restore tissue integrity and mitochondrial physiology at the whole-organ level. Examination of liver, testis, and cerebellum suggest, however, that the precise balance point of fusion and fission is cell type specific.

Published
2015

12. Overcoming the Hypoxic Barrier to Radiation Therapy with Anaerobic Bacteria

Author

Bettegowda, Chetan, Dang, Long H., Abrams, Ross, Huso, David L., Dillehay, Larry, Cheong, Ian, Agrawal, Nishant, Borzillary, Scott, McCaffery, J. Michael, Watson, E. Latice, Lin, Kuo-Shyan, Bunz, Fred, Baidoo, Kwamena, Pomper, Martin G., Kinzler, Kenneth W., Vogelstein, Bert, and Zhou, Shibin

Published
2003

19. Mitochondrial mislocalization and altered assembly of a cluster of Barth syndrome mutant tafazzins

Author

Claypool, Steven M, McCaffery, J Michael, and Koehler, Carla M

Subjects
Pediatric, Congenital Structural Anomalies, Aetiology, 2.1 Biological and endogenous factors, Abnormalities, Multiple, Acyltransferases, Epitopes, Mitochondria, Mitochondrial Membranes, Models, Biological, Mutant Proteins, Mutation, Protein Structure, Quaternary, Protein Transport, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Syndrome, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

None of the 28 identified point mutations in tafazzin (Taz1p), which is the mutant gene product associated with Barth syndrome (BTHS), has a biochemical explanation. In this study, endogenous Taz1p was localized to mitochondria in association with both the inner and outer mitochondrial membranes facing the intermembrane space (IMS). Unexpectedly, Taz1p does not contain transmembrane (TM) segments. Instead, Taz1p membrane association involves a segment that integrates into, but not through, the membrane bilayer. Residues 215-232, which were predicted to be a TM domain, were identified as the interfacial membrane anchor by modeling four distinct BTHS mutations that occur at conserved residues within this segment. Each Taz1p mutant exhibits altered membrane association and is nonfunctional. However, the basis for Taz1p dysfunction falls into the following two categories: (1) mistargeting to the mitochondrial matrix or (2) correct localization associated with aberrant complex assembly. Thus, BTHS can be caused by mutations that alter Taz1p sorting and assembly within the mitochondrion, indicating that the lipid target of Taz1p is resident to IMS-facing leaflets.

Published
2006

46. PNPASE Regulates RNA Import into Mitochondria

Author

Wang, Geng, Chen, Hsiao-Wen, Oktay, Yavuz, Zhang, Jin, Allen, Eric L., Smith, Geoffrey M., Fan, Kelly C., Hong, Jason S., French, Samuel W., McCaffery, J. Michael, Lightowlers, Robert N., Morse, Herbert C., III, Koehler, Carla M., and Teitell, Michael A.

Published
2010
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