Generation of mitochondrial reactive oxygen species is controlled by ATPase inhibitory factor 1 and regulates cognition.
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...
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2021-05-01
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Series: | PLoS Biology |
Online Access: | https://doi.org/10.1371/journal.pbio.3001252 |
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doaj-3c469b3a87654a168245043c7e61234d2021-07-02T19:34:58ZengPublic Library of Science (PLoS)PLoS Biology1544-91731545-78852021-05-01195e300125210.1371/journal.pbio.3001252Generation of mitochondrial reactive oxygen species is controlled by ATPase inhibitory factor 1 and regulates cognition.Pau B Esparza-MoltóInés Romero-CarramiñanaCristina Núñez de ArenasMarta P PereiraNoelia BlancoBeatriz PardoGeorgina R BatesCarla Sánchez-CastilloRafael ArtuchMichael P MurphyJosé A EstebanJosé M CuezvaThe 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.https://doi.org/10.1371/journal.pbio.3001252 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Pau B Esparza-Moltó Inés Romero-Carramiñana Cristina Núñez de Arenas Marta P Pereira Noelia Blanco Beatriz Pardo Georgina R Bates Carla Sánchez-Castillo Rafael Artuch Michael P Murphy José A Esteban José M Cuezva |
spellingShingle |
Pau B Esparza-Moltó Inés Romero-Carramiñana Cristina Núñez de Arenas Marta P Pereira Noelia Blanco Beatriz Pardo Georgina R Bates Carla Sánchez-Castillo Rafael Artuch Michael P Murphy José A Esteban José M Cuezva Generation of mitochondrial reactive oxygen species is controlled by ATPase inhibitory factor 1 and regulates cognition. PLoS Biology |
author_facet |
Pau B Esparza-Moltó Inés Romero-Carramiñana Cristina Núñez de Arenas Marta P Pereira Noelia Blanco Beatriz Pardo Georgina R Bates Carla Sánchez-Castillo Rafael Artuch Michael P Murphy José A Esteban José M Cuezva |
author_sort |
Pau B Esparza-Moltó |
title |
Generation of mitochondrial reactive oxygen species is controlled by ATPase inhibitory factor 1 and regulates cognition. |
title_short |
Generation of mitochondrial reactive oxygen species is controlled by ATPase inhibitory factor 1 and regulates cognition. |
title_full |
Generation of mitochondrial reactive oxygen species is controlled by ATPase inhibitory factor 1 and regulates cognition. |
title_fullStr |
Generation of mitochondrial reactive oxygen species is controlled by ATPase inhibitory factor 1 and regulates cognition. |
title_full_unstemmed |
Generation of mitochondrial reactive oxygen species is controlled by ATPase inhibitory factor 1 and regulates cognition. |
title_sort |
generation of mitochondrial reactive oxygen species is controlled by atpase inhibitory factor 1 and regulates cognition. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS Biology |
issn |
1544-9173 1545-7885 |
publishDate |
2021-05-01 |
description |
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. |
url |
https://doi.org/10.1371/journal.pbio.3001252 |
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