{"doi":"10.1101/2025.05.15.654206","title":"A cold-inducible phospholipid—protein interaction in brown fat mitochondria optimizes thermogenic capacity","abstract":"Cold stress elicits dynamic remodeling of the mitochondrial lipidome in brown adipose tissue (BAT), marked by an increase in arachidonoyl–phosphatidylethanolamine (AA–PE). However, the function of membrane lipid rewiring in thermoregulatory physiology has been a longstanding mystery. Here, we identify LPCAT3 as a cold–regulated O–acyltransferase driving the highly selective accrual of AA–PE in BAT mitochondria. Lipid–based proteomics, molecular dynamics simulations, and bioenergetic analyses reveal that AA–PE partitions at the COX4I1 interface of the Cytochrome c oxidase complex, enhancing electron transport chain (ETC) efficiency. Accordingly, fat–specific Lpcat3 –knockout mice have defects in respiratory–dependent BAT thermogenesis and cold tolerance, despite intact β–adrenergic signaling and UCP1 function. Under cold acclimation, Lpcat3 –/– BAT exhibits ETC dysfunction and activation of the integrated stress-response. Thus, our study illuminates a cold-regulated lipid—protein interaction as a gating factor in UCP1–dependent thermogenesis.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":557942,"datarank":0.10397207708399181,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.0,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9516,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1457969,"name":"Marc J. 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