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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\u2010FLRN\u201042 residues, inducing ceramide\u2010mediated mitophagy. P17\/PERMIT\u2010CerS1\u2010mediated mitophagy attenuated the argininosuccinate\/fumarate\/malate axis and induced <jats:sc>d<\/jats:sc>\u2010glucose and fructose accumulation in neurons in culture and brain tissues (primarily in the cerebellum) of wild\u2010type mice in vivo. These metabolic changes in response to sodium\u2010selenite were nullified in the cerebellum of CerS1to\/to (catalytically inactive for C18\u2010ceramide production CerS1 mutant), PARKIN\u2212\/\u2212 or p17\/PERMIT\u2212\/\u2212 mice that have dysfunctional mitophagy. Whereas sodium selenite induced mitophagy in the cerebellum and improved motor\u2010neuron deficits in aged wild\u2010type mice, exogenous fumarate or malate prevented mitophagy. Attenuating ceramide\u2010mediated mitophagy enhanced damaged mitochondria accumulation and age\u2010dependent sensorimotor abnormalities in p17\/PERMIT\u2212\/\u2212 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\u2212\/\u2212 mice. Thus, these data describe the metabolic consequences of alterations to p17\/PERMIT\/ceramide\u2010mediated mitophagy associated with the loss of mitochondrial quality control in neurons and provide therapeutic options to overcome age\u2010dependent sensorimotor deficits and related disorders like amyotrophic lateral sclerosis (ALS).<\/jats:p>","DOI":"10.1111\/acel.13954","type":"journal-article","created":{"date-parts":[[2023,8,24]],"date-time":"2023-08-24T05:44:59Z","timestamp":1692855899000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Alterations of lipid\u2010mediated mitophagy result in aging\u2010dependent sensorimotor defects"],"prefix":"10.1111","volume":"22","author":[{"given":"Natalia","family":"Oleinik","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Medical University of South Carolina  Charleston South Carolina USA"},{"name":"Hollings Cancer Center Medical University of South Carolina  Charleston South Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Onder","family":"Albayram","sequence":"additional","affiliation":[{"name":"Departments of Pathology and Laboratory Medicine Medical University of South Carolina  Charleston South Carolina USA"},{"name":"Department of Neuroscience Medical University of South Carolina  Charleston South Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3501-1802","authenticated-orcid":false,"given":"Mohamed Faisal","family":"Kassir","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Medical University of South Carolina  Charleston South Carolina USA"},{"name":"Hollings Cancer Center Medical University of South Carolina  Charleston South Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F. 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USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Kurtz","sequence":"additional","affiliation":[{"name":"Departments of Pathology and Laboratory Medicine Medical University of South Carolina  Charleston South Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Alekseyenko","sequence":"additional","affiliation":[{"name":"Hollings Cancer Center Medical University of South Carolina  Charleston South Carolina USA"},{"name":"Public Health Medical University of South Carolina  Charleston South Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Habeeb","family":"Alsudani","sequence":"additional","affiliation":[{"name":"Cancer Center Cold Spring Harbor Laboratory  Cold Spring Harbor New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megan","family":"Sheridan","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology 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