Differences in relative capacities of oxidative phosphorylation pathways may explain sex- and tissue-specific...

Mitochondrial dysfunction is a major cause and/or contributor to the development and progression of vision defects in many ophthalmologic and mitochondrial diseases. Despite their mechanistic commonality, these diseases exhibit an impressive variety in sex- and tissue-specific penetrance, incidence, and severity. Currently, there is no functional explanation for these differences. We measured the function, relative capacities, and patterns of control of various oxidative phosphorylation pathways in the retina, the eyecup, the extraocular muscles, the optic nerve, and the sciatic nerve of adult male and female rats. We show that the control of mitochondrial respiratory pathways in the visual system is sex- and tissue-specific and that this may be an important factor in determining susceptibility to mitochondrial dysfunction between these groups. The optic nerve showed a low relative capacity of the NADH pathway, depending on complex I, compared to other tissues relying mainly on mitochondria for energy production. Furthermore, NADH pathway capacity is higher in females compared to males, and this sexual dimorphism occurs only in the optic nerve. Our results propose an explanation for Leber's hereditary optic neuropathy, a mitochondrial disease more prevalent in males where the principal tissue affected is the optic nerve. To our knowledge, this is the first study to identify and provide functional explanations for differences in the occurrence and severity of visual defects between tissues and between sexes. Our results highlight the importance of considering sex- and tissue-specific mitochondrial function in elucidating pathophysiological mechanisms of visual defects.