Key result
ATP6AP2 knockdown in retinal pigment epithelium cells reduced pyruvate dehydrogenase activity and shifted metabolism toward anaerobic glycolysis by destabilizing the PDH E1 β subunit.
Why the study?
Does ATP6AP2 knockdown reduce PDH activity and alter glucose metabolism in RPE cells?
Does ATP6AP2 knockdown reduce PDH activity and alter glucose metabolism in RPE cells?
ATP6AP2 functions as a PDHB stabilizer, playing a crucial role in aerobic glucose metabolism and oxidative stress regulation in the retina.
ATP6AP2 may regulate RPE aerobic metabolism via PDHB; hypothesis-generating for retinal disorders, requiring validation before clinical consideration.
Background: The mechanism of efficient energy generation in the highly evolved mammalian retina remains incompletely understood. Results: ATP6PA2 interacts with the E1 β subunit of pyruvate dehydrogenase, a key enzyme in aerobic energy generation, controlling its protein stability. Conclusion: ATP6AP2 contributes to glucose metabolism together with oxidative stress. Significance: The present data provide a novel insight into the biological function of ATP6AP2 in the retina. Aerobic glucose metabolism is indispensable for metabolically active cells; however, the regulatory mechanism of efficient energy generation in the highly evolved mammalian retina remains incompletely understood. Here, we revealed an unsuspected role for (pro)renin receptor, also known as ATP6AP2, in energy metabolism. Immunoprecipitation and mass spectrometry analyses identified the pyruvate dehydrogenase (PDH) complex as Atp6ap2-interacting proteins in the mouse retina. Yeast two-hybrid assays demonstrated direct molecular binding between ATP6AP2 and the PDH E1 β subunit (PDHB). Pdhb immunoreactivity co-localized with Atp6ap2 in multiple retinal layers including the retinal pigment epithelium (RPE). ATP6AP2 knockdown in RPE cells reduced PDH activity, showing a predilection to anaerobic glycolysis. ATP6AP2 protected PDHB from phosphorylation, thus controlling its protein stability. Down-regulated PDH activity due to ATP6AP2 knockdown inhibited glucose-stimulated oxidative stress in RPE cells. Our present data unraveled the novel function of ATP6AP2/(P)RR as a PDHB stabilizer, contributing to aerobic glucose metabolism together with oxidative stress.
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Kanda et al. (2015) studied Energy metabolism in the mammalian retina. ATP6AP2 knockdown was evaluated on Pyruvate dehydrogenase (PDH) activity and protein stability. ATP6AP2 knockdown in retinal pigment epithelium cells reduced pyruvate dehydrogenase activity and shifted metabolism toward anaerobic glycolysis by destabilizing the PDH E1 β subunit.
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