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Alterations of lipid-mediated mitophagy result in aging-dependent sensorimotor defects |
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| Authors: | Natalia Oleinik Onder Albayram Mohamed Faisal Kassir F. Cansu Atilgan Chase Walton Eda Karakaya John Kurtz Alexander Alekseyenko Habeeb Alsudani Megan Sheridan Zdzislaw M. Szulc Besim Ogretmen |
| Affiliation: | 1. Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina, USA;2. Departments of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina, USA Department of Neuroscience, Medical University of South Carolina, Charleston, South Carolina, USA;3. Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina, USA Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina, USA;4. Departments of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina, USA;5. Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina, USA Public Health, Medical University of South Carolina, Charleston, South Carolina, USA;6. Cancer Center, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA |
| Abstract: | The 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). |
| Keywords: | aging ceramide CerS1 Drp1 mitochondrial metabolism mitophagy neurodegeneration sensorimotor defects |