Food derived respiratory complex I inhibitors modify the effect of Leber hereditary optic neuropathy mutations.

Abstract Mitochondrial DNA mutations in genes encoding respiratory complex I polypeptides can cause Leber hereditary optic neuropathy. Toxics affecting oxidative phosphorylation system can also cause mitochondrial optic neuropathy. Some complex I inhibitors found in edible plants might differentially interact with these pathologic mutations and modify their penetrance. To analyze this interaction, we have compared the effect of rotenone, capsaicin and rolliniastatin-1 on cybrids harboring the most frequent Leber hereditary optic neuropathy mutations and found that m.3460G > A mutation increases rotenone resistance but capsaicin and rolliniastatin-1 susceptibility. Thus, to explain the pathogenicity of mitochondrial diseases due to mitochondrial DNA mutations, their potential interactions with environment factors will have to be considered. Highlights • Some mitochondrial DNA (mtDNA) mutations cause Leber hereditary optic neuropathy (LHON). • Some oxidative phosphorylation system inhibitors cause mitochondrial optic neuropathies. • Food derived xenobiotics modify the penetrance of LHON mtDNA mutations. • The m.3460G > A mutation increases rotenone resistance but capsaicin and rolliniastatin-1 susceptibility. • Gene-environment interactions must be considered to explain mitochondrial disease pathogenicity. [ABSTRACT FROM AUTHOR]