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

Abstract

Müller 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.

The ketogenic diet and hypoxia promote mitophagy in the context of glaucoma

“…Both OHT and the ketogenic diet promote mitophagy in the RGCs and Müller glia of the mouse retina. For RGCs, where oxidative phosphorylation plays a larger role in metabolic homeostasis than in Müller glia ( Nsiah and Inman, 2022 ), the ketogenic diet promoted mitophagy beyond that which occurred with OHT. We also directly showed that cells exposed to acute hypoxia upregulate mitophagy.…”

Downregulated expression of lactate dehydrogenase in adult oligodendrocytes and its implication for the transfer of glycolysis products to axons

“…Also, the reanalyses of snRNAseq and scRNAseq data from wildtype mice (Ximerakis et al, 2019;Zhou et al, 2020) suggest that both Ldh transcripts are expressed markedly less in mature myelinating oligodendrocytes compared to neurons and astrocytes (Figure 2j,k). Interestingly, metabolic stress that increases glycolytic metabolism and LDHA expression in other systems, including mitochondrial dysfunction in mice with Cox10-deficiency in neurons or Müller cells (Garcia et al, 2022;Nsiah & Inman, 2022), did not induce LDH expression in mature Cox10-deficient oligodendrocytes (Figure 4e), revealing a remarkable lack of metabolic plasticity.…”