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

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Brunetta, Henver S. ; Jung, Anna S. ; Valdivieso-Rivera, Fernando ; Zani, Stepheny C. de Campos ; Guerra, Joel ; Furino, Vanessa O. ; Francisco, Annelise ; Bercot, Marcelo ; Moraes-Vieira, Pedro M. ; Keipert, Susanne ; Jastroch, Martin ; Martinez, Laurent O. ; Sponton, Carlos H. ; Castilho, Roger F. ; Mori, Marcelo A. ; Bartelt, Alexander

• Document type: Journal article
• Source: EMBO Journal; v. 43, n. 21, p. 22-pg., 2024-09-16.

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. How the hydrolytic activity of mitochondrial ATP synthase is modulated during brown adipose tissue (BAT) thermogenesis remains unexplored. This study demonstrates that reduction of inhibitory factor 1 (IF1) upon cold conditions facilitates the reverse mode activity of ATP synthase for bioenergetic adaptation during thermogenesis.IF1 depletion in mouse BAT following cold exposure increases hydrolytic activity of ATP synthase.IF1 overexpression in brown adipocytes impairs maintenance of the mitochondrial membrane potential upon adrenergic stimulation.IF1 overexpression in BAT of mice impairs non-shivering thermogenesis induced by beta 3-adrenergic agonists. Reduction of Inhibitory Factor 1 in brown adipose tissue during cold exposure enables bioenergetic adaptation during thermogenesis. (AU)

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