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

Area of Science:

• Biochemistry
• Genetics
• Toxicology

Background:

• Mitochondrial DNA (mtDNA) mutations in complex I genes are a primary cause of Leber hereditary optic neuropathy (LHON).
• Environmental toxins impacting the oxidative phosphorylation system can also induce mitochondrial optic neuropathy.
• Plant-derived complex I inhibitors may interact with pathogenic mtDNA mutations, potentially modifying disease penetrance.

Purpose of the Study:

• To investigate the differential effects of complex I inhibitors (rotenone, capsaicin, rolliniastatin-1) on cybrids with common LHON-associated mtDNA mutations.
• To determine if specific mutations influence susceptibility or resistance to these environmental toxins.

Main Methods:

• Utilized cybrid cell models harboring common Leber hereditary optic neuropathy mutations.
• Exposed cybrids to rotenone, capsaicin, and rolliniastatin-1 to assess their effects on mitochondrial function and cell viability.
• Analyzed the interaction between the m.3460G>A mutation and the tested inhibitors.

Main Results:

• The m.3460G>A mutation conferred increased resistance to rotenone.
• Conversely, the m.3460G>A mutation led to heightened susceptibility to capsaicin and rolliniastatin-1.
• These findings indicate mutation-specific responses to environmental complex I inhibitors.

Conclusions:

• The pathogenicity of mitochondrial diseases, such as LHON, is influenced by interactions between mtDNA mutations and environmental factors.
• Environmental exposures, like specific plant compounds, can modulate the clinical presentation and severity of inherited mitochondrial optic neuropathies.
• A comprehensive understanding of mitochondrial disease mechanisms requires consideration of both genetic predisposition and environmental influences.