IF1 is a cold-regulated switch of ATP synthase hydrolytic activity to support thermogenesis in brown fat
Year: 2024
Type: article
Abstract: 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.
Source: The EMBO Journal
Authors: Henver S Brunetta, Anna S Jung, Fernando Valdivieso-Rivera, Stepheny C de Campos Zani, Joel Guerra, Vanessa O Furino, Annelise Francisco, Marcelo Berçot, Pedro M Moraes-Vieira, Susanne Keipert, Martin Jastroch, Laurent O Martinez, Carlos H Sponton, Roger F Castilho, Marcelo A Mori, Alexander Bartelt
Institutions: Universidade Estadual de Campinas (UNICAMP), Institut für Prophylaxe und Epidemiologie der Kreislaufkrankheiten, Ludwig-Maximilians-Universität München, Helmholtz Munich, Stockholm University, Université Toulouse III - Paul Sabatier, Inserm, Institut des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse, German Center for Diabetes Research
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $6,890
Awards: G1094477216, G116629194, G1740861664, G1901460537, G1910733787, Mitochondrial function and dysfunction: implications for aging and associated diseases, G295657101, G3478773369, G393381764, G4321390119, G4509857914, G5954978330, G6068289979, G6438247056, G6815844370, G6826893353, G7319221454, The interplay between the immune system and metabolism as a key determinant of the aging process, G7564048527, G7901828625, G8226292163
OpenAlex ID: W4402581278