biostudies-literatureBrunetta HSDeutsche Forschungsgemeinschaft (DFG)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)European Research CouncilConselho Nacional de Desenvolvimento Científico e TecnológicoDeutsche ForschungsgemeinschaftDeutsches Zentrum für Herz-KreislaufforschungCoordenação de Aperfeiçoamento de Pessoal de Nível SuperiorFundação de Amparo à Pesquisa do Estado de São PauloConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Deutsches Zentrum für Herz-Kreislaufforschung (DZHK)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)4870-4891https://www.ebi.ac.uk/biostudies/studies/S-EPMC11535227biostudies-literatureUnknown43(21)While mechanisms controlling uncoupling protein-1 (UCP1) in thermogenic adipocytes play a pivotal role in non-shivering thermogenesis, it remains unclear whether F₁Fo-ATP synthase function is also regulated in brown adipose tissue (BAT). Here, we show that inhibitory factor 1 (IF1, encoded by Atp5if1), an inhibitor of ATP synthase hydrolytic activity, is a critical negative regulator of brown adipocyte energy metabolism. In vivo, IF1 levels are diminished in BAT of cold-adapted mice compared to controls. Additionally, the capacity of ATP synthase to generate mitochondrial membrane potential (MMP) through ATP hydrolysis (the so-called "reverse mode" of ATP synthase) is increased in brown fat. In cultured brown adipocytes, IF1 overexpression results in an inability of mitochondriaThe EMBO journalIF1 is a cold-regulated switch of ATP synthase hydrolytic activity to support thermogenesis in brown fat.PMC11535227310287/2018-98527422022/00358-188881.143924/2017-01BA4925/2-181X3600212Valdivieso-Rivera FFrancisco AFurino VOKeipert SBrunetta HSCastilho RFJastroch MBercot MGuerra JMartinez LOde Campos Zani SCMori MAMoraes-Vieira PMBartelt AJung ASSponton CHfalseIF1 is a cold-regulated switch of ATP synthase hydrolytic activity to support thermogenesis in brown fat.While mechanisms controlling uncoupling protein-1 (UCP1) in thermogenic adipocytes play a pivotal role in non-shivering thermogenesis, it remains unclear whether F₁Fo-ATP synthase function is also regulated in brown adipose tissue (BAT). Here, we show that inhibitory factor 1 (IF1, encoded by Atp5if1), an inhibitor of ATP synthase hydrolytic activity, is a critical negative regulator of brown adipocyte energy metabolism. In vivo, IF1 levels are diminished in BAT of cold-adapted mice compared to controls. Additionally, the capacity of ATP synthase to generate mitochondrial membrane potential (MMP) through ATP hydrolysis (the so-called "reverse mode" of ATP synthase) is increased in brown fat. In cultured brown adipocytes, IF1 overexpression results in an inability of mitochondria2024-01-01T00:00:00Z2024 Nov2026-07-16T13:20:06.325Z2025-04-20T03:55:41.315ZS-EPMC115352273928490910.1038/s44318-024-00215-0