Generation of mitochondrial reactive oxygen species is controlled by ATPase inhibitory factor 1 and regulates cognition.
Núñez de Arenas, Cristina
Public Library of Science (PLoS)
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Esparza-Moltó, P. B., Romero-Carramiñana, I., Núñez de Arenas, C., Pereira, M. P., Blanco, N., Pardo, B., Bates, G. R., et al. (2021). Generation of mitochondrial reactive oxygen species is controlled by ATPase inhibitory factor 1 and regulates cognition.. PLoS Biol, 19 (5), e3001252. https://doi.org/10.1371/journal.pbio.3001252
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.
Brain, Hippocampus, Cell Line, Mitochondria, Animals, Mice, Inbred C57BL, Mice, Reactive Oxygen Species, Mitochondrial Proton-Translocating ATPases, Proteins, Adenosine Triphosphate, Signal Transduction, Primary Cell Culture
Wellcome Trust (220257/Z/20/Z)
Medical Research Council (MC_UU_00015/3)
External DOI: https://doi.org/10.1371/journal.pbio.3001252
This record's URL: https://www.repository.cam.ac.uk/handle/1810/322911
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