Alterations of lipid‐mediated mitophagy result in aging‐dependent sensorimotor defects

Abstract

AbstractThe metabolic consequences of mitophagy alterations due to age‐related stress in healthy aging brains versus neurodegeneration remain unknown. Here, we demonstrate that ceramide synthase 1 (CerS1) is transported to the outer mitochondrial membrane by the p17/PERMIT transporter that recognizes mislocalized mitochondrial ribosomes (mitoribosomes) via 39‐FLRN‐42 residues, inducing ceramide‐mediated mitophagy. P17/PERMIT‐CerS1‐mediated mitophagy attenuated the argininosuccinate/fumarate/malate axis and induced d‐glucose and fructose accumulation in neurons in culture and brain tissues (primarily in the cerebellum) of wild‐type mice in vivo. These metabolic changes in response to sodium‐selenite were nullified in the cerebellum of CerS1to/to (catalytically inactive for C18‐ceramide production CerS1 mutant), PARKIN−/− or p17/PERMIT−/− mice that have dysfunctional mitophagy. Whereas sodium selenite induced mitophagy in the cerebellum and improved motor‐neuron deficits in aged wild‐type mice, exogenous fumarate or malate prevented mitophagy. Attenuating ceramide‐mediated mitophagy enhanced damaged mitochondria accumulation and age‐dependent sensorimotor abnormalities in p17/PERMIT−/− mice. Reinstituting mitophagy using a ceramide analog drug with selenium conjugate, LCL768, restored mitophagy and reduced malate/fumarate metabolism, improving sensorimotor deficits in old p17/PERMIT−/− mice. Thus, these data describe the metabolic consequences of alterations to p17/PERMIT/ceramide‐mediated mitophagy associated with the loss of mitochondrial quality control in neurons and provide therapeutic options to overcome age‐dependent sensorimotor deficits and related disorders like amyotrophic lateral sclerosis (ALS).