{"doi":"10.1093/pnasnexus/pgae018","title":"p17/C18-ceramide–mediated mitophagy is an endogenous neuroprotective response in preclinical and clinical brain injury","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.","journal":"PNAS Nexus","year":2024,"id":437780,"datarank":0.3596842909197557,"base_score":2.3978952727983707,"endowment":2.3978952727983707,"self_citation_contribution":0.3596842909197557,"citation_network_contribution":0.0,"self_endowment_contribution":0.3596842909197557,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":10,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9562,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":877844,"name":"Natalia V. Oleinik","orcid":"0000-0002-6658-9140","position":1,"is_corresponding":false},{"id":1247270,"name":"Jazlyn Edwards","orcid":"0009-0009-2981-4028","position":2,"is_corresponding":false},{"id":1193671,"name":"Jensen Tomberlin","orcid":null,"position":3,"is_corresponding":false},{"id":1247271,"name":"R. Barker","orcid":"0009-0008-7258-9498","position":4,"is_corresponding":false},{"id":1247272,"name":"Burak Berber","orcid":"0000-0001-5136-5323","position":5,"is_corresponding":false},{"id":18916,"name":"Maria Ericsson","orcid":"0000-0002-4563-3683","position":6,"is_corresponding":false},{"id":760029,"name":"Habeeb Alsudani","orcid":"0000-0002-0630-0800","position":7,"is_corresponding":false},{"id":270142,"name":"Adviye Ergul","orcid":"0000-0003-0873-6015","position":8,"is_corresponding":false},{"id":39709,"name":"Semir Beyaz","orcid":"0000-0003-4730-4012","position":9,"is_corresponding":false},{"id":342793,"name":"John J. Lemasters","orcid":"0000-0002-7627-6295","position":10,"is_corresponding":false},{"id":593575,"name":"Besim Öğretmen","orcid":"0000-0002-1019-5660","position":11,"is_corresponding":false},{"id":651809,"name":"Önder Albayram","orcid":"0000-0002-2028-1458","position":12,"is_corresponding":false},{"id":918497,"name":"Eda Karakaya","orcid":"0000-0003-4156-3785","position":0,"is_corresponding":true}],"reference_count":111,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:00:34.490087Z","pmid":"38328780","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}