Rod photoreceptor-specific deletion of MPC1 impairs visual function with age-dependent retinal degeneration

Abstract

Purpose : Mitochondrial pyruvate carrier (MPC) transports pyruvate from glycolysis into mitochondria. We recently reported pan-retinal deletion of MPC1 (a major component of MPC) disrupts retinal metabolism and causes retinal degeneration. In this study, we aim to understand the role of MPC in rod photoreceptors

Methods : MPC1 flox/flox mice were crossed with rod photoreceptor cre mice to generate mice with rod-specific deletion of MPC1 (RMPC1^-/-). We measured visual function by electroretinogram (ERG), retinal thickness by optical coherence tomography (OCT) and H&E, protein expression by immunohistochemistry, ultrastructure by electron microscope (EM), and retinal metabolites by targeted metabolomics and metabolic flux analysis

Results : Immunostaining with a customized antibody confirms the specific deletion of MPC1 in rod photoreceptors in RMPC^-/- mice. Scotopic a-wave and b-wave decrease in RMPC1^-/- mice starting at postnatal 30 days (P30), and further decline at P60. However, RMPC1^-/- mice show a late-onset photoreceptor degeneration after P90. Photoreceptor inner segments are partially damaged in EM but the expression of mitochondrial complexes is normal. Pyruvate and aspartate accumulate, but citrate, glutamate and glutamine remain at normal amounts in RMPC1^-/- retinas, suggesting metabolic compensation by other cells and/or nutrients. Consistently, the expression of GFAP and glutamine synthetase is upregulated in Müller glial cells. To study whether an alternative fuel could rescue the phenotype, we fed the mice with a ketogenic diet for 2 months starting at P21. The ketogenic diet significantly improves scotopic ERGs in RMPC1^-/- mice in the first month but there is no protection after two months.

Conclusions : Mitochondrial pyruvate transport in photoreceptors is essential for visual function and photoreceptor viability. Although mitochondria have the flexibility to use a variety of nutrients, pyruvate, mostly from glycolysis, is indispensable for normal rod function and survival.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.