Arsenic induced mitochondrial DNA damage and altered mitochondrial oxidative function: implications for genotoxic mechanisms in mammalian cells.
Arsenic is a well-established human carcinogen that is chronically consumed in drinking water by millions of people worldwide. Recent evidence has suggested that arsenic is a genotoxic carcinogen. Furthermore, we have shown that mitochondria mediate the mutagenic effects of arsenic in mammalian cells, as arsenic did not induce nuclear mutations in mitochondrial DNA (mtDNA)-depleted cells. Using the human-hamster hybrid A(L) cells, we show here that arsenic alters mitochondrial function by decreasing cytochrome c oxidase function and oxygen consumption but increasing citrate synthase function. These alterations correlated with depletion in mtDNA copy number and increase in large heteroplasmic mtDNA deletions. In addition, mtDNA isolated periodically from cultures treated continuously with arsenic did not consistently display the same deletion pattern, indicating that the mitochondrial genome was subjected to repeated and continuous damage. These data support the theory that the mitochondria, and particularly mtDNA, are important targets of the mutagenic effects of arsenic in mammalian cells.
Partridge
Michael A
MA
Center for Radiological Research, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.
Huang
Sarah X L
SX
Hernandez-Rosa
Evelyn
E
Davidson
Mercy M
MM
Hei
Tom K
TK
D000818:Animals; D001151:Arsenic / Q000633:toxicity*; D006224:Cricetinae; D004249:DNA Damage; D004272:DNA, Mitochondrial / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D003576:Electron Transport Complex IV / Q000378:metabolism; D006801:Humans; D006822:Hybrid Cells; D008928:Mitochondria / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D009152:Mutagenicity Tests; D010084:Oxidation-Reduction; D010101:Oxygen Consumption / Q000187:drug effects
D004272:DNA, Mitochondrial; D003576:Electron Transport Complex IV; D001151:Arsenic