IF1 is a cold-regulated switch of ATP synthase hydrolytic activity to support thermogenesis in brown fat

Brunetta, Henver S; Jung, Anna S; Valdivieso-Rivera, Fernando; de Campos Zani, Stepheny C; Guerra, Joel; Furino, Vanessa O; Francisco, Annelise; Berçot, Marcelo; Moraes-Vieira, Pedro M; Keipert, Susanne; Jastroch, Martin; Martinez, Laurent O; Sponton, Carlos H; Castilho, Roger F; Mori, Marcelo A; Bartelt, Alexander (2024): IF1 is a cold-regulated switch of ATP synthase hydrolytic activity to support thermogenesis in brown fat. The EMBO Journal, 43 (21). pp. 4870-4891. ISSN 1460-2075

Abstract

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 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.

• Doc-Type: Article (LMU)
• Organisational unit (Faculties): 07 Medicine > Medical Center of the University of Munich > Institute for Prophylaxis and Epidemiology of Circulatory Diseases (IPEK)
• DFG subject classification of scientific disciplines: Life sciences
• DFG: Funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) - 238187445
• DFG: Funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) - 461705523
• DFG: Funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) - 491502892