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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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2019-02, Vol.116 (9), p.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: Article
Language:English
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
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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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1812941116