Carlos T. Moraes
Associate Professor of Neurology and Cell Biology and Anatomy
Ph.D. (1993) Columbia University
Human Genetics; Molecular Pathogenesis of Disease-Related Mitochondrial DNA Mutations

Although mitochondrial genetics of yeast and trypanosomes has been extensively explored in 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.

Large-scale rearrangements and point mutations of mtDNA have been associated with devastating clinical syndromes. Organs with high energy requirements such as brain and muscle are preferentially affected. Symptoms include: seizures, strokes, muscle weakness, blindness, diabetes, and hearing loss. In addition to defining novel mtDNA abnormalities in patients with mitochondrial disorders, we are interested in understanding the molecular pathogenesis of these mutations. We use a full array of molecular and cell biology techniques to analyze mitochondrial gene expression both in patients' tissues and in transmitochondrial cell lines. We are particularly interested in the consequences of tRNA mutations on mitochondrial protein synthesis. Novel approaches to gene therapy for mitochondrial disorders are also being developed in our laboratory. Besides bona-fide mitochondrial diseases, we are analyzing the role of mitochondrial dysfunction in age-related neurodegenerative disorders.

We are also interested in the role a mitochondrial dysfunction could have in cancer progression and apoptosis. Recent results from different groups suggest that mtDNA mutations may confer a growth advantage in certain tumors. Nuclear-mitochondrial communication as well as the consequences of disrrupted interactions in xenomitochondrial cells and animals is also a topic being actively investigated in our laboratory.

Mitochondrial Genetics & Biology Group (2001)




PICTURES OF FORMER LAB MEMBERS

    Representative Publications
Moraes CT, Ciacci F, Bonilla E, Ionascescu V, Schon EA and DiMauro S (1993) A mitochondrial tRNA anticodon swap associated with a muscle disease. Nature Genetics 4, 284-287.

Hao H, Bonilla E, Manfredi G, DiMauro S, Moraes CT (1995) Segregation patterns of a novel mutation in the mitochondrial tRNA glutamic acid gene associated with myopathy and diabetes mellitus. American Journal of Human Genetics 56, 1017-1025.

Hao H and Moraes CT (1996) Functional and molecular mitochondrial abnormalities associated with a C->T transition at position 3256 of the human mitochondrial genome. Journal of Biological Chemistry 271, 2347-2352.

Hao, H., Manfredi, G., Moraes, C. T. (1997) Functional and structural features of a tandem duplication of the human mitochondrial DNA promoter region. American Journal of Human Genetics 60:1363-1372

Lesley Kenyon and Carlos T. Moraes. (1997) Expanding the functional human mitochondrial DNA database by the establishment of primate xenomitochondrial cybrids. Proceedings of the National Academy of Sciences USA 94:9131-9135

Ashok Verma, David A. Piccoli, Eduardo Bonilla, Gerard T. Berry, Salvatore DiMauro, and Carlos T. Moraes (1997) A Novel Mitochondrial G8313A Mutation Associated with Prominent Initial Gastrointestinal Symptoms and Progressive Encephaloneuropathy Pediatric Research 42:448-454

C.H. Tengan, A.A. Gabbai, S. Shanske, M. Zeviani, C.T. Moraes (1997). Oxidative phosphorylation dysfunction does not increase the rate of accumulation of age-related mtDNA deletions in skeletal muscle. Mutation Research 379:1-11

H. Hao and C.T. Moraes (1997) A Disease-Associated G5703A Mutation in the Human Mitochondrial DNA Causes a Conformational Change and a Marked Decrease in Steady-State Levels of the Mitochondrial tRNA-Asn. Molecular and Cellular Biology 17:6831-6837

A. Barrientos, L. Kenyon, C. T. Moraes (1998) Human Xenomitochondrial Cybrids: Cellular Models of Mitochondrial Complex I Deficiency. The Journal of Biological Chemistry 273: 14210-14217

A. Barrientos, and C. T. Moraes (1998) Simultaneous transfer of mitochondrial DNA and single chromosomes in somatic cells: a novel approach for the study of defects in nuclear-itochondrial communication. Human Molecular Genetics. 7: 1801-1808

Huiling Hao, Lawrence E. Morrison, and Carlos T. Moraes (1999) Suppression of a Mitochondrial tRNA Gene Mutation Phenotype Associated with Changes in the Nuclear Background. Human Molecular Genetics. 8:1117-1124

Antoni Barrientos and Carlos T. Moraes (1999) Titrating the Effects of Mitochondrial Complex I Impairment in the Cell Physiology. Journal of Biological Chemistry. 274: 16188-16197

Carlos T. Moraes, Lesley Kenyon and Huiling Hao (1999) Mechanisms of Human Mitochondrial DNA Maintenance: The Determining Role of Primary Sequence and Length over Function. Molecular Biology of the Cell 10:3345-3356

Lack of Oxidative Phosphorylation and Low Mitochondrial Membrane Potential Decrease Susceptibility to Apoptosis and Do not Modulate the Protective Effect of Bcl-xL in Osteosarcoma Cells.
Dey, R. and Moraes, C.T. J. Biol. Chem. 275:7087-7094 (2000)

Mitochondrial function in heart muscle from patients with idiopathic dilated cardiomyopathy. Jarreta D., Orus J., Barrientos A., Miro O, Roig E., Heras M., Moraes C.T., Cardellach F., Casademont J. Cardiovasc Res. 45:860-5 (2000).

A Novel Myopathy-Associated mtDNA Mutation Altering the Conserved Size of the tRNAGln Anticodon Loop.
Runu Dey, Celia H. Tengan, Maria P.A. Morita, Beatriz H. Kiyomoto and Carlos T. Moraes
Neuromuscular Disorders 10:488-492 (2000).

Functional Constraints of Nuclear - Mitochondrial DNA Interactions in Xeno-mitochondrial Rodent Cell Lines
Runu Dey, Antoni Barrientos, and Carlos T. Moraes J Biol Chem, 275: 31520-31527 (2000).

Cloning of an Endangered Species (Bos gaurus) Using Interspecies Nuclear Transfer
Robert P. Lanza, Jose B. Cibelli, Francisca Diaz, Carlos T. Moraes, Peter W. Farin, Charlotte E. Farin, Carolyn J. Hammer, Michael D. West & Philip Damiani Cloning, 2:79-88 (2000).

Cytochrome c Oxidase Assembly in Primates is Sensitive to Small Evolutionary Variations in Amino Acid Sequence
Antoni Barrientos, Stefan Müller, Runu Dey, Johannes Wienberg and Carlos T. Moraes
Molecular Biology and Evolution, 17: 1508-1519 (2000)

An out of Frame Cytochrome b Gene Deletion from a Patient with Parkinsonism is Associated with Impaired Complex III Assembly and Increase in Free Radicals Production
Michele Rana, Irenaeus de Coo, Francisca Diaz, Hubert Smeets, and Carlos T. Moraes
Annals of Neurology;48:774-781 (2000).

What regulates mitochondrial DNA copy number in animal cells?
Moraes, C. T. Trends Genet 17, 199-205. (2001)



Honors and Professional Activities
PEW Scholar in the Biomedical Sciences (1995-1999)
Member of the American Society of Human Genetics

Currently Funded Research:

Carlos T. Moraes, Ph.D.
1501 NW 9th Avenue
Miami, FL 33136
(305) 243-5858
cmoraes@med.miami.edu
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WWW links related to mitochondrial genetics and Moraes' research

Monkey mtDNA in human cells (AP news release)
MtDNA database and information
Department of Neurology UM
Pedro's Molecular Biology Research Tools

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