title: Heteroplasmic mutations of the mitochondrial genome cause paradoxical effects on mitochondrial functions.
abstract: Mitochondrial genome (mtDNA) mutation causes highly variable clinical features, and its pathogenesis is not fully understood. In this study, we analyzed the heteroplasmic mtDNA mutation C4936T (p.T156I) in ND2 of complex I and the homoplasmic mtDNA mutation A9181G (p.S219G) in ATPase 6 of complex V. Using cybrid technology, we found that in a high-glucose medium in which cultured cells mainly depend on anaerobic glycolysis for energy, the C4936T mutation inhibited cell growth by 50%. Oxygen consumption and reactive oxygen species production were also reduced by 60 and 75%, respectively. Because the subject also had conjunctiva carcinoma, we further tested whether the C4936T mutation was associated with tumor formation. In an anchorage-dependant growth test, we found that only cells with a high level of C4936T mutation formed colonies. In contrast, when the cells grew in a galactose medium in which cells were forced to generate ATP through oxidative phosphorylation, the C4936T mutation protected cells from apoptosis probably caused by the A9181G mutation. Our results suggest that the phenotype caused by mtDNA mutations may depend on the availability of the nutrients. This gene-environment interaction may contribute to the complexity of pathogenesis and clinical phenotypes caused by mtDNA mutation.
authors.affiliation: Department of Pediatrics, University of California-Irvine, Irvine, CA 92697, USA.
authors.forename: Chengkang
authors.initials: C
authors.lastname: Zhang
authors.forename: Vincent H
authors.initials: VH
authors.lastname: Huang
authors.forename: Mariella
authors.initials: M
authors.lastname: Simon
authors.forename: Lokendra K
authors.initials: LK
authors.lastname: Sharma
authors.forename: Weiwei
authors.initials: W
authors.lastname: Fan
authors.forename: Richard
authors.initials: R
authors.lastname: Haas
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Wallace
authors.forename: Yidong
authors.initials: Y
authors.lastname: Bai
authors.forename: Taosheng
authors.initials: T
authors.lastname: Huang
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism; D000328:Adult; D017209:Apoptosis / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D042967:Electron Transport Complex I / Q000235:genetics / Q000378:metabolism; D005690:Galactose / Q000494:pharmacology; D054629:Genome, Mitochondrial / Q000235:genetics*; D006801:Humans; D006822:Hybrid Cells / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism*; D028361:Mitochondrial Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D025261:Mitochondrial Proton-Translocating ATPases; D010085:Oxidative Phosphorylation / Q000187:drug effects; D010101:Oxygen Consumption / Q000235:genetics; D017354:Point Mutation; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D008565:Membrane Proteins; D017382:Reactive Oxygen Species; D000251:Adenosine Triphosphatases; D025261:Mitochondrial Proton-Translocating ATPases; D042967:Electron Transport Complex I; C020439:oligomycin sensitivity-conferring protein; D005690:Galactose