Generation of mitochondrial reactive oxygen species is controlled by ATPase inhibitory factor 1 and regulates cognition

• DOI: 10.1371/journal.pbio.3001252
• Publication Date: 2021-05-13T18:11:01Z
• Authors: Pau B. Esparza-Moltó; Inés Romero-Carra...; Cristina Núñez de...; Marta P. Pereira; Noelia Blanco; Beatriz Pardo; Georgina R. Bates; Carla Sánchez-Cas...; Rafael Artuch; Michael P. Murphy; José A. Esteban; José M. Cuezva
• Keywords: 0301 basic medicine; QH301-705.5; Primary Cell Culture; ATPase Inhibitory Protein; Engineering and technology; Hippocampus; Cell Line; Mice; 03 medical and health sciences; Adenosine Triphosphate; Reactive Oxygen Metabolite; Animals; Biology (General); Medicine and health sciences; 0303 health sciences; Biology and life sciences; Brain; Proteins; Hydrogen Peroxide; Mitochondrial Proton-Translocating ATPases; Biología y Biomedicina / Biología; FOS: Engineering and technology; Mitochondrial DNA; Mitochondria; Adenosine Diphosphate; Research and analysis methods; Mice, Inbred C57BL; Reactive Oxygen Species; Research Article; Signal Transduction

The mitochondrial ATP synthase emerges as key hub of cellular functions controlling the production of ATP, cellular signaling, and fate. It is regulated by the ATPase inhibitory factor 1 (IF1), which is highly abundant in neurons. Herein, we ablated or overexpressed IF1 in mouse neurons to show that IF1 dose defines the fraction of active/inactive enzyme in vivo, thereby controlling mitochondrial function and the production of mitochondrial reactive oxygen species (mtROS). Transcriptomic, proteomic, and metabolomic analyses indicate that IF1 dose regulates mitochondrial metabolism, synaptic function, and cognition. Ablation of IF1 impairs memory, whereas synaptic transmission and learning are enhanced by IF1 overexpression. Mechanistically, quenching the IF1-mediated increase in mtROS production in mice overexpressing IF1 reduces the increased synaptic transmission and obliterates the learning advantage afforded by the higher IF1 content. Overall, IF1 plays a key role in neuronal function by regulating the fraction of ATP synthase responsible for mitohormetic mtROS signaling.