bioRxiv. 2025 May 18. pii: 2025.05.15.654206. [Epub ahead of print]
Yuta Shimanaka,
Marcus J Tol,
Christian Rocha-Roa,
Matthew J Jellinek,
Liujuan Cui,
Aaron Bender,
Alexander H Bedard,
Madeleine G Milner,
Bruno Melillo,
Bassem M Shoucri,
Adrian Wong,
Kevin J Williams,
Linsey Stiles,
Michael Shum,
Thomas A Weston,
Whitaker Cohn,
Julian P Whitelegge,
Itay Budin,
Ambre M Bertholet,
Benjamin F Cravatt,
Stephen G Young,
Sander M Houten,
Carmen Argmann,
David A Ford,
Marc Liesa,
Orian S Shirihai,
Stefano Vanni,
Peter Tontonoz.
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.