Mitochondrial DNA-deficient models and aging.
Human mitochondrial DNA (mtDNA) encodes 13 subunits of oxidative phosphorylation (OXPHOS) enzyme complexes I, III, IV, and V except complex II. MtDNA is more sensitive to oxidative damage than nuclear DNA. MtDNA defects are involved in many pathologies including aging. Several mtDNA-deficient cell culture, yeast, and animal models were generated to study the role of mtDNA in many physiological processes. Ethidium bromide (EB), an agent that is known to inhibit mtDNA replication with a negligible effect on nuclear DNA, is generally used to generate mtDNA-deficient models. The antibiotics chloramphenicol and doxycycline, which were known to inhibit mitochondrial translation, were also used to generate the same phenotype. Cultured mtDNA-deficient cells need uridine and pyruvate to survive. At the organismal level, uridine can be supplemented, but pyruvate supplementation can cause a worser phenotype because of lactic acidosis. In C. elegans, EB, when used during larval development, increases life span, but decreases, when used after the beginning of adult stage. This should be kept in mind since mitochondria-related genes are generally detected in genome-wide screening studies for longevity. We believe that conditional knockout studies need to be carried out for these genes after reaching adulthood. MtDNA mutator mouse did not show an increase of free radical production. Therefore, the downstream phenomena to mtDNA defects are likely ineffective pyrimidine synthesis (dihydroorotate dehydrogenase, DHODH, needs a functional respiratory chain) and excess NADH (decreased NAD pool) in addition to free radicals.
Olgun
Abdullah
A
Department of Biochemistry and Clinical Biochemistry, Gülhane School of Medicine, 06018 Etlik, Ankara, Turkey. aolgun@yahoo.com
Akman
Serif
S
D000375:Aging / Q000235:genetics*; D000818:Animals; D017173:Caenorhabditis elegans; D002467:Cell Nucleus / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000378:metabolism; D004195:Disease Models, Animal; D004996:Ethidium / Q000494:pharmacology; D005609:Free Radicals; D006801:Humans; D008136:Longevity; D051379:Mice; D009154:Mutation; D010100:Oxygen / Q000378:metabolism; D010641:Phenotype; D010766:Phosphorylation
D004272:DNA, Mitochondrial; D005609:Free Radicals; D004996:Ethidium; D010100:Oxygen