The mitochondrial encephalomyopathies are a clinically, morphologically, and biochemically diverse group of disorders. In the past several years, specific mitochondrial DNA (mtDNA) mutations have been found to result in several human diseases. Unfortunately, there has been little or no correlation between the identification of the mtDNA mutations, the presumed etiology, and the pathogenesis of these disorders. The goal of this proposal is to analyze the pathological consequences and the molecular genetic causes of several specific mtDNA mutations causing human disease. This analysis will take advantage of a unique cell culture system that permits the analysis of mtDNA mutations in a neutral nuclear background. This system is based upon the isolation of human cell lines that completely lack mtDNA (p/o cell lines) and the ability to repopulate these cells with exogenous mitochondria, and thus, mtDNA. This system will be applied to the analysis of the disease MERRF (myoclonic epilepsy and ragged-red fiber disease). Two point mutations, both in tRNA/LYS of the mtDNA, are known to result in this disease. By examining the biochemical, morphological and genetic consequences of these two mutations, and comparing the results, it should be possible to determine the precise molecular mechanism of pathogenesis. In a similar fashion, other point mutations of the mtDNA-encoded tRNA genes associated with disease will be studied. Only after specific defects and their causes are known, will it be possible to develop rational therapies for patients suffering from these diseases. This in vitro system will permit the exact metabolic requirements for cells with impaired respiratory chain function to be determined. In addition, the effects of different growth conditions or treatments on the mutated and wild-type mtDNAs can be examined. If one genome can be preferentially damaged or inhibited in its replication, it may be possible to devise treatments for these currently incurable, and often fatal diseases. In addition to those diseases being studied in this proposal, this model system can also be applied to the study of other diseases where mitochondrial involvement is known or suspected, and the proposed analyses will provide a foundation for these future characterizations.

Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Columbia University (N.Y.)
New York
United States
Zip Code
Barca, Emanuele; Ganetzky, Rebecca D; Potluri, Prasanth et al. (2018) USMG5 Ashkenazi Jewish founder mutation impairs mitochondrial complex V dimerization and ATP synthesis. Hum Mol Genet 27:3305-3312
Pera, Marta; Larrea, Delfina; Guardia-Laguarta, Cristina et al. (2017) Increased localization of APP-C99 in mitochondria-associated ER membranes causes mitochondrial dysfunction in Alzheimer disease. EMBO J 36:3356-3371
Fryer, Robert H; Bain, Jennifer M; De Vivo, Darryl C (2016) Mitochondrial Encephalomyopathy Lactic Acidosis and Stroke-Like Episodes (MELAS): A Case Report and Critical Reappraisal of Treatment Options. Pediatr Neurol 56:59-61
Varma, Hemant; Faust, Phyllis L; Iglesias, Alejandro D et al. (2016) Whole exome sequencing identifies a homozygous POLG2 missense variant in an infant with fulminant hepatic failure and mitochondrial DNA depletion. Eur J Med Genet 59:540-5
Piekutowska-Abramczuk, Dorota; Kocy?a-Karczmarewicz, Beata; Ma?kowska, Maja et al. (2016) No Evidence for Association of SCO2 Heterozygosity with High-Grade Myopia or Other Diseases with Possible Mitochondrial Dysfunction. JIMD Rep 27:63-8
Cloonan, Suzanne M; Glass, Kimberly; Laucho-Contreras, Maria E et al. (2016) Mitochondrial iron chelation ameliorates cigarette smoke-induced bronchitis and emphysema in mice. Nat Med 22:163-74
Engelstad, Kristin; Sklerov, Miriam; Kriger, Joshua et al. (2016) Attitudes toward prevention of mtDNA-related diseases through oocyte mitochondrial replacement therapy. Hum Reprod 31:1058-65
Ripolone, Michela; Ronchi, Dario; Violano, Raffaella et al. (2015) Impaired Muscle Mitochondrial Biogenesis and Myogenesis in Spinal Muscular Atrophy. JAMA Neurol 72:666-75
Quinzii, Catarina M; Hirano, Michio; DiMauro, Salvatore (2014) Mutant COQ2 in multiple-system atrophy. N Engl J Med 371:81-2
Area-Gomez, Estela; Schon, Eric A (2014) Mitochondrial genetics and disease. J Child Neurol 29:1208-15

Showing the most recent 10 out of 241 publications