Reduced complex I activity in the retinal pigment epithelium, but not in rod photoreceptors, affects light signaling without impacting cell survival.

Mutations in the mitochondrial respiratory complex I accessory subunit NADH:ubiquinone oxidoreductase subunit S4 (ndufs4) can cause the mitochondrial disease Leigh syndrome, which may be associated with vision loss. We previously demonstrated that mice with global deletion of ndufs4 exhibited impaired in vivo photoreceptor light responses prior to the early death of the mice around postnatal day 50. However, ex vivo electrophysiology recordings performed on retinas from ndufs4 mice were normal, suggesting that the in vivo phenotype may reflect altered homeostasis of the extracellular environment of photoreceptors rather than their intrinsic metabolic dysfunction. To test this hypothesis, we have generated mouse strains with cell-specific deletions of ndufs4 from rod photoreceptors and from the retinal pigment epithelium (RPE), a key supporting cell to photoreceptors. We now demonstrate that despite efficient depletion of NDUFS4 protein and consequent reduction of complex I activity in rods, scotopic electroretinography (ERG) responses are essentially normal and rod survival is not impacted by rod-specific ndufs4 deletion. Interestingly, while RPE-specific deletion of ndufs4 depletes NDUFS4 protein and reduces complex I activity in RPE, a ∼15% reduction in ERG amplitudes is observed, much less than the 50% reduction previously reported in global ndufs4 mice. This suggests that a more complex metabolic relationship exists between photoreceptors, RPE, and other cells of the retina to establish the homeostatic physiological conditions necessary for normal light signaling.