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Arsenic is an important environmental carcinogen that affects millions of people worldwide through contaminated water supplies. For decades, arsenic was considered a nongenotoxic carcinogen. Using the highly sensitive A_L mutation assay, we previously showed that arsenic is, indeed, a potent gene and chromosomal mutagen and that its effects are mediated through the induction of reactive oxygen species. However, the origin of these radicals and the pathways involved are not known. Here we show that mitochondrial damage plays a crucial role in arsenic mutagenicity. Treatment of enucleated cells with arsenic followed by rescue fusion with karyoplasts from controls resulted in significant mutant induction. In contrast, treatment of mitochondrial DNA–depleted (ρ⁰) cells produced few or no mutations. Mitochondrial damage can lead to the release of superoxide anions, which then react with nitric oxide to …