Loss of MPC1 reprograms retinal metabolism to impair visual function

Glucose metabolism in vertebrate retinas is dominated by aerobic glycolysis (the “Warburg Effect”), which allows only a small fraction of glucose-derived pyruvate to enter mitochondria. Here, we report evidence that the small fraction of pyruvate in photoreceptors that does get oxidized by their mit...

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Published in:	Proceedings of the National Academy of Sciences - PNAS Vol. 116; no. 9; pp. 3530 - 3535
Main Authors:	Grenell, Allison, Wang, Yekai, Yam, Michelle, Swarup, Aditi, Dilan, Tanya L., Hauer, Allison, Linton, Jonathan D., Philp, Nancy J., Gregor, Elizabeth, Zhu, Siyan, Shi, Quan, Murphy, Joseph, Guan, Tongju, Lohner, Daniel, Kolandaivelu, Saravanan, Ramamurthy, Visvanathan, Goldberg, Andrew F. X., Hurley, James B., Dua, Jianhai
Format:	Journal Article
Language:	English
Published:	United States National Academy of Sciences 26-02-2019
Subjects:	Animals Biological Sciences Degeneration Glucose Glucose - metabolism Glutamine Glycolysis Glycolysis - genetics Homeostasis Humans Metabolism Metabolomics Mice Mitochondria Mitochondria - genetics Mitochondria - metabolism Mitochondrial Membrane Transport Proteins - genetics Mitochondrial Membrane Transport Proteins - metabolism Monocarboxylic Acid Transporters Neuronal-glial interactions Photoreception Photoreceptors Pyruvic acid Pyruvic Acid - metabolism Retina Retina - metabolism Retina - pathology Retinal Cone Photoreceptor Cells - metabolism Retinal Cone Photoreceptor Cells - pathology Retinal Degeneration Retinal Rod Photoreceptor Cells - metabolism Retinal Rod Photoreceptor Cells - pathology Structure-function relationships Tracers Vertebrates Viability Vision, Ocular - genetics Visual perception MPC retinal degeneration glutamine pyruvate mitochondrial metabolism
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Summary:	Glucose metabolism in vertebrate retinas is dominated by aerobic glycolysis (the “Warburg Effect”), which allows only a small fraction of glucose-derived pyruvate to enter mitochondria. Here, we report evidence that the small fraction of pyruvate in photoreceptors that does get oxidized by their mitochondria is required for visual function, photoreceptor structure and viability, normal neuron–glial interaction, and homeostasis of retinal metabolism. The mitochondrial pyruvate carrier (MPC) links glycolysis and mitochondrial metabolism. Retina-specific deletion of MPC1 results in progressive retinal degeneration and decline of visual function in both rod and cone photoreceptors. Using targeted-metabolomics and 13C tracers, we found that MPC1 is required for cytosolic reducing power maintenance, glutamine/glutamate metabolism, and flexibility in fuel utilization.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Author contributions: J.B.H. and J.D. designed research; A.G., Y.W., M.Y., A.S., T.L.D., J.D.L., N.J.P., E.G., S.Z., J.M., T.G., D.L., S.K., V.R., A.F.X.G., and J.D. performed research; A.G., Y.W., M.Y., A.S., T.L.D., A.H., N.J.P., E.G., S.Z., Q.S., A.F.X.G., and J.D. analyzed data; and A.G., J.B.H., and J.D. wrote the paper. Edited by Matthew G. Vander Heiden, Koch Institute at Massachusetts Institute of Technology, and accepted by Editorial Board Member Jeremy Nathans January 14, 2019 (received for review July 26, 2018)
ISSN:	0027-8424 1091-6490
DOI:	10.1073/pnas.1812941116