Destabilizing COXIV in Muller Glia Increases Retinal Glycolysis and Alters Scotopic Electroretinogram

Muller glia (MG), the principal glial cell of the retina, have a metabolism that defies categorization into glycolytic versus oxidative. We showed that MG mount a strong hypoxia response to ocular hypertension, raising the question of their relative reliance on mitochondria for function. To explore the role of oxidative phosphorylation (OXPHOS) in MG energy production in vivo, we generated and characterized adult mice in which MG have impaired cytochrome c oxidase (COXIV) activity through knockout of the COXIV constituent COX10. Histochemistry and protein analysis showed that COXIV protein levels were significantly lower in knockout mouse retina compared to control. Loss of COXIV activity in MG did not induce structural abnormalities, though oxidative stress was increased. Electroretinography assessment showed that knocking out COX10 significantly impaired scotopic a- and b-wave responses. Inhibiting mitochondrial respiration in MG also altered the retinal glycolytic profile. However, blocking OXPHOS in MG did not significantly exacerbate retinal ganglion cell (RGC) loss or photopic negative response after ocular hypertension (OHT). These results suggest that MG were able to compensate for reduced COXIV stability by maintaining fundamental processes, but changes in retinal physiology and metabolism-associated proteins indicate subtle changes in MG function.

Automated summary

Muller glia (MG) cells in the retina have a unique metabolism that cannot be categorized into glycolytic or oxidative. When subjected to ocular hypertension, MG show a strong hypoxia response, which raises questions about their reliance on mitochondria for energy production. In this study, researchers found that knocking out a key component of the mitochondria in MG cells did not cause structural abnormalities, but did increase oxidative stress. Electroretinography assessment showed impaired responses in the retina of these knockout mice. Blocking mitochondrial respiration in MG cells also altered the glycolytic profile of the retina. However, blocking oxidative phosphorylation did not significantly worsen retinal ganglion cell loss or the photopic negative response after ocular hypertension. These findings suggest that MG cells are able to compensate for impaired mitochondrial function, but there are subtle changes in their function and retinal physiology.