title: ATP6AP2/(pro)renin receptor contributes to glucose metabolism via stabilizing the pyruvate dehydrogenase E1 β subunit.
abstract: 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.
authors.affiliation: From the Department of Ophthalmology, Laboratory of Ocular Cell Biology and Visual Science, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido 060-8638, Japan.
authors.forename: Atsuhiro
authors.initials: A
authors.lastname: Kanda
authors.affiliation: From the Department of Ophthalmology, Laboratory of Ocular Cell Biology and Visual Science, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido 060-8638, Japan.
authors.forename: Kousuke
authors.initials: K
authors.lastname: Noda
authors.affiliation: From the Department of Ophthalmology, Laboratory of Ocular Cell Biology and Visual Science, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido 060-8638, Japan ishidasu@med.hokudai.ac.jp.
authors.forename: Susumu
authors.initials: S
authors.lastname: Ishida
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005947:Glucose / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D016253:Microscopy, Immunoelectron; D011485:Protein Binding; D055550:Protein Stability; D030481:Pyruvate Dehydrogenase (Lipoamide) / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D012160:Retina / Q000378:metabolism / Q000648:ultrastructure; D055213:Retinal Pigment Epithelium / Q000166:cytology / Q000378:metabolism; D020798:Two-Hybrid System Techniques; D025262:Vacuolar Proton-Translocating ATPases / Q000235:genetics / Q000378:metabolism*; D000093342:Prorenin Receptor
chemical_list: D005947:Glucose; D030481:Pyruvate Dehydrogenase (Lipoamide); D011956:Receptors, Cell Surface; D025262:Vacuolar Proton-Translocating ATPases; C458319:ATP6AP2 protein, human; D000093342:Prorenin Receptor; C111305:pyruvate dehydrogenase E1 beta subunit
keywords: (Pro)renin Receptor; ATP6AP2; Glucose Metabolism; Pyruvate Dehydrogenase Complex (PDC); Renin Angiotensin System; Retina; Retinal Metabolism