Electron transport chain activity balances cell cycle progression and differentiation of retinal progenitor cells

The retina is considered one of the most metabolically active tissues in the mammalian central nervous system. Prior studies have defined the extent of metabolic diversity among all seven adult retinal cell types. However, the specific metabolic changes in retinal progenitor cells (RPCs) during development remain unknown. In this study, we characterized the histochemical patterns of oxidative phosphorylation (OXPHOS) and glycolysis indicators in the differentiating and maturing mouse retina. Also, by performing RPC-specific conditional knockout (CKO) of the mitochondrial transcription factor A (Tfam), we generated retinas in which RPC OXPHOS activity was lost throughout retinogenesis. We found that early-stage (embryonic) Tfam CKO RPCs were completely OXPHOS-deficient yet underwent normal proliferation, cell cycle exit, and differentiation into retinal neurons. In contrast, late-stage (postnatal) RPCs remained in a proliferative state well past the normal developmental period, leading to a later reduction in the generation of bipolar cells and Müller glia. Ultimately, as the CKO retina fully matures, it becomes severely hypoplastic due to cell death that we attribute to the previous loss of bipolar cells and Müller glia. In total, our data establishes that, over time, RPCs exhibit heterogeneity in their metabolic requirements, with the second wave of RPCs being more reliant on OXPHOS activity to undergo proper neurogenesis.