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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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 CSHL Cancer Center Program CSHL Cancer Center Program > Cancer Genetics and Genomics Program |
| SWORD Depositor: | CSHL Elements |
| Depositing User: | CSHL Elements |
| Date: | February 2024 |
| Date Deposited: | 16 Feb 2024 15:45 |
| Last Modified: | 28 May 2024 18:26 |
| PMCID: | PMC10847724 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/41436 |
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