Loss of mitochondrial pyruvate carrier 1 in the retina causes retinal degeneration by disrupting mitochondrial metabolism

Abstract

Purpose : Photoreceptors have active aerobic glycolysis and mitochondrial oxidative metabolism. Mitochondrial pyruvate carrier (MPC) transports pyruvate from glycolysis into mitochondria where the citric acid cycle (CAC) takes place. We generated mice with retina-specific deletion of MPC1 to study the role of mitochondrial pyruvate transport in photoreceptor function and metabolism.

Methods : MPC1 floxed mice were crossed with Six3-Cre mice to yield mice with retina specific deletion of MPC1 (MPC-/-). Visual function was evaluated by electroretinography (ERG). Retinal morphology was determined by H&E staining, optical coherence tomography (OCT) and immunofluorescence. Retinal metabolism was quantified using LC MS/MS and GC-MS.

Results : MPC-/- mice had a 30-40% reduction in both scotopic and photopic ERG response when compared with littermate controls at postnatal day 30 (P30). At P90 animals displayed a 50-70% reduction. OCT and histology indicated that MPC-/- had progressive retinal degeneration, primarily within the outer segment layer. Immunostaining with rhodopsin and peanut agglutinin revealed a short and disorganized photoreceptor layer. Pyruvate and aspartate accumulated, while glutamate, glutamine, 3-hydroxybutyrate, NADPH and glutathione decreased in the MPC-/- retina. Surprisingly, lactate and ATP remained unchanged. The retinas lacking MPC diminished the flux of carbon from ¹³C glucose into mitochondria to generate citrate, glutamate and glutamine. However, the flux of carbons from neither ¹³C glutamine or ¹³C 3-hydroxybutyrate significantly increased in MPC deficient retinas.

Conclusions : Loss of MPC1 disrupts the regulation of amino acid synthesis and redox balance within the mitochondria resulting in retinal degeneration. Mitochondrial pyruvate transport is essential for maintaining the integrity of photoreceptor outer segments.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.