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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Detalles Bibliográficos
Autores: Esparza Molto, Pau Bernat, Romero Carramiñana, Inés, Núñez de Arenas Flores, Cristina, Pérez Pereira, Marta, Blanco Menéndez, Noelia, Pardo Merino, Beatriz, Bates, Georgina R., Sánchez Castillo, Carla, Artuch, Rafael, Murphy, Michael P., Esteban, José Antonio, Cuezva Marcos, José Manuel
Tipo de recurso: artículo
Fecha de publicación:2021
País:España
Institución:Universidad Autónoma de Madrid
Repositorio:Biblos-e Archivo. Repositorio Institucional de la UAM
Idioma:inglés
OAI Identifier:oai:repositorio.uam.es:10486/705765
Acceso en línea:http://hdl.handle.net/10486/705765
https://dx.doi.org/10.1371/journal.pbio.3001252
Access Level:acceso abierto
Palabra clave:Adenosine Diphosphate
Adenosine Triphosphate
Hydrogen Peroxide
Mitochondrial DNA
ATPase Inhibitory Protein
Reactive Oxygen Metabolite
Biología y Biomedicina / Biología
Descripción
Sumario: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

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