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

  • Aging Cell. 2023 Oct;22(10):e13954. doi: 10.1111/acel.13954.
Natalia Oleinik  1  2 ,  Onder Albayram  3  4 ,  Mohamed Faisal Kassir  1  2 ,  F Cansu Atilgan  1  2 ,  Chase Walton  1  2 ,  Eda Karakaya  3 ,  John Kurtz  3 ,  Alexander Alekseyenko  2  5 ,  Habeeb Alsudani  6 ,  Megan Sheridan  1  2 ,  Zdzislaw M Szulc  1  2 ,  Besim Ogretmen  1  2
Affiliations
  • 1. Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina, USA.
  • 2. Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina, USA.
  • 3. Departments of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina, USA.
  • 4. Department of Neuroscience, Medical University of South Carolina, Charleston, South Carolina, USA.
  • 5. Public Health, Medical University of South Carolina, Charleston, South Carolina, USA.
  • 6. Cancer Center, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA.
PMID: 37614052 DOI: 10.1111/acel.13954
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
CerS1; Drp1; aging; ceramide; mitochondrial metabolism; mitophagy; neurodegeneration; sensorimotor defects.
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