2. Academic Validation
  3. Alterations of lipid-mediated mitophagy result in aging-dependent sensorimotor defects

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

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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