ArticleAging cell2023
Alterations of lipid-mediated mitophagy result in aging-dependent sensorimotor defects.
Article in Aging cell, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 17 citations in OpenAlex.
- CERS1 is a biomarker of Staphylococcus aureus abundance and atopic dermatitis severity.The Journal of allergy and clinical immunology · 2025Trial
- Mechanisms and Therapeutic Potential of Targeting Mitophagy in Neurodegenerative Diseases.Molecular neurobiology · 2026Review
- Mitophagy in the pathogenesis and management of disease.Cell research · 2026Review
- Alzheimer's Disease-Associated Amyloid-β Precursor Protein Prevents Aging Stress-Induced Mitophagy and Fumarate Depletion to Improve Antitumor Immunity.Cancer research · 2025Article
- Ceramide-Induced Metabolic Stress Depletes Fumarate and Drives Mitophagy to Mediate Tumor Suppression.Cancer research · 2025Article
- Beyond the Pseudogene: p17/PERMIT as a Mitochondrial Trafficking Protein Linking Aging and Neurodegeneration.Aging cell · 2025Article
- Mitochondrial Damage and Autophagy Dysregulation in Alzheimer's Disease: Mechanisms and Therapeutic Opportunities.Neurochemical research · 2025Review
- Fasting the mitochondria to prevent neurodegeneration: the role of ceramides.Frontiers in neuroscience · 2025Review
- Mitochondria as the central regulator of cell death in bronchopulmonary dysplasia.Frontiers in physiology · 2025Review
- Review
- p17/C18-ceramide-mediated mitophagy is an endogenous neuroprotective response in preclinical and clinical brain injury.PNAS nexus · 2024Article
- Alterations of lipid-mediated mitophagy result in aging-dependent sensorimotor defects.Aging cell · 2023Article
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Authors and funding
12 authors at 2 institutions in 1 country.
Funding
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).
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.