{"doi":"10.1016/j.celrep.2021.109076","title":"Aging-dependent mitochondrial dysfunction mediated by ceramide signaling inhibits antitumor T cell response","abstract":"We lack a mechanistic understanding of aging-mediated changes in mitochondrial bioenergetics and lipid metabolism that affect T cell function. The bioactive sphingolipid ceramide, induced by aging stress, mediates mitophagy and cell death; however, the aging-related roles of ceramide metabolism in regulating T cell function remain unknown. Here, we show that activated T cells isolated from aging mice have elevated C14/C16 ceramide accumulation in mitochondria, generated by ceramide synthase 6, leading to mitophagy/mitochondrial dysfunction. Mechanistically, aging-dependent mitochondrial ceramide inhibits protein kinase A, leading to mitophagy in activated T cells. This aging/ceramide-dependent mitophagy attenuates the antitumor functions of T cells in vitro and in vivo. Also, inhibition of ceramide metabolism or PKA activation by genetic and pharmacologic means prevents mitophagy and restores the central memory phenotype in aging T cells. Thus, these studies help explain the mechanisms behind aging-related dysregulation of T cells' antitumor activity, which can be restored by inhibiting ceramide-dependent mitophagy.","journal":"Cell Reports","year":2021,"id":150591,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":91,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9534,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":433527,"name":"Paramita Chakraborty","orcid":"0000-0002-0320-8697","position":1,"is_corresponding":false},{"id":640340,"name":"Han Gyul Lee","orcid":"0009-0003-8351-9130","position":2,"is_corresponding":false},{"id":362164,"name":"Alhaji H. Janneh","orcid":"0000-0001-5959-6126","position":3,"is_corresponding":false},{"id":640341,"name":"Mohamed Faisal Kassir","orcid":"0000-0003-3501-1802","position":4,"is_corresponding":false},{"id":229866,"name":"Gyda Beeson","orcid":null,"position":5,"is_corresponding":false},{"id":641316,"name":"Zachariah Hedley","orcid":null,"position":6,"is_corresponding":false},{"id":640342,"name":"Ahmet Yalçınkaya","orcid":"0000-0002-1172-3330","position":7,"is_corresponding":false},{"id":639876,"name":"M. Hanief Sofi","orcid":null,"position":8,"is_corresponding":false},{"id":391286,"name":"Hong Li","orcid":"0000-0002-6065-5100","position":9,"is_corresponding":false},{"id":585731,"name":"Monica L. Husby","orcid":"0000-0002-0176-7241","position":10,"is_corresponding":false},{"id":271705,"name":"Robert V. Stahelin","orcid":"0000-0001-5443-7863","position":11,"is_corresponding":false},{"id":321624,"name":"Xue‐Zhong Yu","orcid":"0000-0002-1751-2884","position":12,"is_corresponding":false},{"id":242937,"name":"Shikhar Mehrotra","orcid":"0000-0002-5411-9504","position":13,"is_corresponding":false},{"id":593575,"name":"Besim Öğretmen","orcid":"0000-0002-1019-5660","position":14,"is_corresponding":false},{"id":641315,"name":"Silvia G. Vaena","orcid":null,"position":0,"is_corresponding":true}],"reference_count":91,"raw_metadata":null,"created_at":"2026-07-18T23:43:06.501849Z","pmid":"33951438","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":[]}