p17/C18-ceramide-mediated mitophagy is an endogenous neuroprotective response in preclinical and clinical brain injury

Karakaya, Eda, Oleinik, Natalia, Edwards, Jazlyn, Tomberlin, Jensen, Barker, Randy Bent, Berber, Burak, Ericsson, Maria, Alsudani, Habeeb, Ergul, Adviye, Beyaz, Semir, Lemasters, John J, Ogretmen, Besim, Albayram, Onder (February 2024) p17/C18-ceramide-mediated mitophagy is an endogenous neuroprotective response in preclinical and clinical brain injury. PNAS Nexus, 3 (2). ISSN 2752-6542

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URL: https://www.ncbi.nlm.nih.gov/pubmed/38328780
DOI: 10.1093/pnasnexus/pgae018

Abstract

Repeat concussions (or repetitive mild traumatic brain injury [rmTBI]) are complex pathological processes consisting of a primary insult and long-term secondary complications and are also a prerequisite for chronic traumatic encephalopathy (CTE). Recent evidence implies a significant role of autophagy-mediated dysfunctional mitochondrial clearance, mitophagy, in the cascade of secondary deleterious events resulting from TBI. C18-ceramide, a bioactive sphingolipid produced in response to cell stress and damage, and its synthesizing enzyme (CerS1) are precursors to selective stress-mediated mitophagy. A transporter, p17, mediates the trafficking of CerS1, induces C18-ceramide synthesis in the mitochondrial membrane, and acts as an elimination signal in cell survival. Whether p17-mediated mitophagy occurs in the brain and plays a causal role in mitochondrial quality control in secondary disease development after rmTBI are unknown. Using a novel repetitive less-than-mild TBI (rlmTBI) injury paradigm, ablation of mitochondrial p17/C18-ceramide trafficking in p17 knockout (KO) mice results in a loss of C18-ceramide-induced mitophagy, which contributes to susceptibility and recovery from long-term secondary complications associated with rlmTBI. Using a ceramide analog with lipid-selenium conjugate drug, LCL768 restored mitophagy and reduced long-term secondary complications, improving cognitive deficits in rlmTBI-induced p17KO mice. We obtained a significant reduction of p17 expression and a considerable decrease of CerS1 and C18-ceramide levels in cortical mitochondria of CTE human brains compared with age-matched control brains. These data demonstrated that p17/C18-ceramide trafficking is an endogenous neuroprotective mitochondrial stress response following rlmTBI, thus suggesting a novel prospective strategy to interrupt the CTE consequences of concussive TBI.

Item Type: Paper
Subjects: organs, tissues, organelles, cell types and functions > organs types and functions > brain
neurobiology
neurobiology > neuroscience
organs, tissues, organelles, cell types and functions > organs types and functions
organs, tissues, organelles, cell types and functions
CSHL Authors:
Communities: CSHL labs > Beyaz lab
CSHL labs > Spector lab
SWORD Depositor: CSHL Elements
Depositing User: CSHL Elements
Date: February 2024
Date Deposited: 16 Feb 2024 15:45
Last Modified: 16 Feb 2024 15:45
PMCID: PMC10847724
Related URLs:
URI: https://repository.cshl.edu/id/eprint/41436

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