Carlos T. Moraes, Ph.D.
Professor of Neurology
Description of Research
Although mitochondrial genetics of yeast and trypanosomes has been extensively explored during the last 20 years, the study of human mitochondrial DNA (mtDNA) gained momentum in 1988 with the discovery of diseases associated with mtDNA mutations. The human mtDNA is a compact circular genome (16.6 kb) coding for components of the ATP-producing oxidative phosphorylation system. Because mtDNA-coded polypeptides are synthesized in mitochondrial-specific ribosomes, the mtDNA also codes for a set of rRNAs and tRNAs necessary for intraorganelle translation. The contribution of the mitochondrial genome to cellular respiration, though vital, is not sufficient. Dozens of nuclear-coded proteins synthesized in the cytoplasm are imported into mitochondria and assembled with mitochondrially-synthesized proteins to form a functional oxidative phosphorylation system.
Recently, mutations in the mtDNA also have been described in a large number of tumors. Dr. Moraes currently is studying the potential role of these mutations in cell signaling and invasion. Mitochondria are also major players in programmed cell death, an important determinant of tumorigenesis. A number of anti-and pro-apoptotic factors seem to mediate their functions in association with mitochondrial membranes. Dr. Moraes and his research team also are exploring the interplay between the role of cytochrome c in respiration and in stimulating apoptosis.
Highlights
- Discovered colorectal tumors with stop codon mutations in the mtDNA develop a compensatory mechanism to upregulate mitochondrial respiration. The mechanism involves the upregulation of PGC-1 family members, which trigger an increase in mitochondrial biogenesis.
- Found that cytochrome c has a major role in promoting TNF-alpha mediated apoptosis in vivo
- Researchers in Dr. Moraes’ laboratory also found that the lack of respiration confers resistance to some apoptosis triggers (e.g., staurosporin) but hypersensitivity to TNF-alpha
Selected Cancer-Related Publications
- Srivastava S, Diaz F, Iommarini L, Aure K, Lombes A, Moraes CT. PGC-1alpha/beta induced expression partially compensates for respiratory chain defects in cells from patients with mitochondrial disorders. Hum Mol Genet 18:1805-1812, 2009. Read more »
- Wenz T, Diaz F, Hernandez D, Moraes CT. Endurance exercise is protective for mice with mitochondrial myopathy. J Appl Physiol 106:1712-9, 2009. Read more »
- Torraco A, Diaz F, Vempati UD, Moraes CT. Mouse models of oxidative phosphorylation defects: Powerful tools to study the pathobiology of mitochondrial diseases. Biochim Biophys Acta 1793:171-80, 2009. Read more »
- Vempati UD, Han X, Moraes CT. Lack of Cytochrome c in Mouse Fibroblasts Disrupts Assembly/Stability of Respiratory Complexes I and IV. J Biol Chem 284:4383-91, 2009. Read more »
- Fukui H, Moraes CT. Mechanisms of formation and accumulation of mitochondrial DNA deletions in aging neurons. Hum Mol Genet 18:1028-36, 2009. Read more »
- Wenz T, Luca C, Torraco A, Moraes CT. mTERF2 regulates oxidative phosphorylation by modulating mtDNA transcription. Cell Metab 9:499-511, 2009. Read more »
- Bacman SR, Williams SL, Moraes CT. Intra- and inter-molecular recombination of mitochondrial DNA after in vivo induction of multiple double-strand breaks. Nucleic Acids Res 37:4218-26, 2009. Read more »
Programs
Collaborating in the Multidisciplinary Research Program(s):