IF1 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 F<sub>1</sub>Fo-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 mitochondria to sustain the MMP upon adrenergic stimulation, leading to a quiescent-like phenotype in brown adipocytes. In mice, adeno-associated virus-mediated IF1 overexpression in BAT suppresses adrenergic-stimulated thermogenesis and decreases mitochondrial respiration in BAT. Taken together, our work identifies downregulation of IF1 upon cold as a critical event for the facilitation of the reverse mode of ATP synthase as well as to enable energetic adaptation of BAT to effectively support non-shivering thermogenesis.
Authors
- Annelise Francisco (ORCID: https://orcid.org/0000-0001-6729-8807)
- Vanessa de Oliveira Furino (ORCID: https://orcid.org/0000-0002-5224-9401)
- Alexander Bartelt (ORCID: https://orcid.org/0000-0001-7840-3991)
- Fernando Valdivieso‐Rivera (ORCID: https://orcid.org/0000-0001-5044-197X)
- Marcelo A. Mori (ORCID: https://orcid.org/0000-0001-7112-5263)
- Carlos H. Sponton (ORCID: https://orcid.org/0000-0003-4284-8176)
- Laurent O. Martinez (ORCID: https://orcid.org/0000-0002-0985-3152)
- Susanne Keipert (ORCID: https://orcid.org/0000-0002-6618-7379)
- Martin Jastroch (ORCID: https://orcid.org/0000-0003-0358-3865)
- Marcelo Rodrigues Berçot (ORCID: https://orcid.org/0000-0003-2803-482X)
- Roger F. Castilho (ORCID: https://orcid.org/0000-0003-2338-8717)
- Henver S. Brunetta (ORCID: https://orcid.org/0000-0002-6052-7838)
- Pedro M. Moraes‐Vieira (ORCID: https://orcid.org/0000-0002-8263-786X)
- Joel Guerra (ORCID: https://orcid.org/0000-0002-7149-3784)
- Anna Jung (ORCID: https://orcid.org/0009-0004-0756-8050)
- Stepheny C de Campos Zani
Institutions
- Université Toulouse III - Paul Sabatier (FR)
- Inserm (FR)
- Stockholm University (SE)
- Universidade Estadual de Campinas (UNICAMP) (BR)
- Helmholtz Zentrum München (DE)
- Centre Hospitalier Universitaire de Toulouse (FR)
- German Centre for Cardiovascular Research (DE)
- Institut des Maladies Métaboliques et Cardiovasculaires (FR)
- Deutsches Diabetes-Zentrum e.V. (DE)
- German Center for Diabetes Research (DE)
- Heinrich Heine University Düsseldorf (DE)
- Ludwig-Maximilians-Universität München (DE)
Publication Details
- Journal
- The EMBO Journal
- Published
- 2024-09-16
- DOI
- https://doi.org/10.1038/s44318-024-00215-0
- Citations
- 9
- Primary Topic
- Adipose Tissue and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 2.94
Funders
- Deutsches Zentrum für Herz-Kreislaufforschung
- Deutsche Forschungsgemeinschaft
- Fundação de Amparo à Pesquisa do Estado de São Paulo
- Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
- Conselho Nacional de Desenvolvimento Científico e Tecnológico
- European Research Council