Mitochondrial Damage Mediates Genotoxicity of Arsenic in Mammalian Cells

Abstract

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 (R 0 ) cells produced few or no mutations. Mitochondrial damage can lead to the release of superoxide anions, which then react with nitric oxide to produce the highly reactive peroxynitrites. The mutagenic damage was dampened by the nitric oxide synthase inhibitor, N G -methyl-L-arginine. These data illustrate that mitochondria are a primary target in arsenic-induced genotoxic response and that a better understanding of the mutagenic/carcinogenic mechanism of arsenic should provide a basis for better interventional approach in both treatment and prevention of arsenic-induced cancer. (Cancer Res 2005; 65(8): 3236-42)

Mitochondrial dysfunction in human pathologies

“…ROS may have a multifactorial origin, mitochondria being one of the possible sources. Arsenic, a well characterized and common carcinogen, damages mitochondria and promotes mitochondrial ROS production (237,238), and the carcinogen benzo(a)pyrene induces mitochondrial dysfunction (239). Importantly, the accumulation of mutations in people not exposed to carcinogens is associated with the presence of peroxidized lipids.…”

Constitutive nitric oxide acting as a possible intercellular signaling molecule in the initiation of radiation-induced DNA double strand breaks in non-irradiated bystander cells

“…In the present studies, we investigated the nature of the DSB-inducing factor(s) and how it was generated and transferred. By treating the cells with L-NMMA to inhibit the NOS activity (Leach et al, 2002;Liu et al, 2005) (D-NMMA), it was found that L-NMMA, could effectively block the DIA of conditioned medium in the receptor cells. In contrast, D-NMMA, the inactive enantiomer had no effect.…”

“…The conditioned medium collected at 10 min post 1 cGy a-particle irradiation was transferred to the medium receptor cells. L-NMMA (Molecular Probes, Eugene, Oregon, USA) has been shown to be an effective NOS inhibitor (Leach et al, 2002;Liu et al, 2005). However, in the presence L-NMMA, the conditioned medium collected at 10 min post-irradiation showed no distinct DIA (15.7-15.1%, P ¼ 0.83) (Figure 1), whereas only a marginal decrease (29.6-26.0%) in DIA was found with D-NMMA Figure 1 Effect of the NOS inhibition, L-NMMA (a NOS inhibitor, 1 mM), D-NMMA (non-reactive D-enantiomer, 1 mM), 7-Ni (a selective cNOS inhibitor, 4 mM) or AG (a selective iNOS inhibitor, 0.1 mM) on the induction of bystander DSBs.…”

Mitochondrial myopathy caused by arsenic trioxide therapy

“…5,6 In mammal cells, arsenic genotoxicity is mainly mediated by mitochondrial damage, including mitochondrial oxidative dysfunction. 7,8 Here we report a patient with APL who developed a delayed, severe, and partially reversible mitochondrial myopathy after being treated with ATO. …”