1. Generation of mitochondrial reactive oxygen species is controlled by ATPase inhibitory factor 1 and regulates cognition
- Author
-
Inés Romero-Carramiñana, Carla Sánchez-Castillo, Rafael Artuch, José M. Cuezva, Noelia Blanco, Georgina Bates, Pau B. Esparza-Moltó, José A. Esteban, Beatriz Pardo, Michael P. Murphy, Marta P. Pereira, Cristina Núñez de Arenas, UAM. Departamento de Biología Molecular, Esparza-Moltó, Pau B. [0000-0001-9034-1121], Pereira, Marta P. [0000-0002-9347-957X], Blanco, Noelia [0000-0002-2487-228X], Bates, Georgina R. [0000-0002-6574-5164], Esteban, José A. [0000-0002-3759-3300], Cuezva, José M. [0000-0003-1118-248X], Apollo - University of Cambridge Repository, Esparza-Moltó, Pau B [0000-0001-9034-1121], Pereira, Marta P [0000-0002-9347-957X], Bates, Georgina R [0000-0002-6574-5164], Esteban, José A [0000-0002-3759-3300], and Cuezva, José M [0000-0003-1118-248X]
- Subjects
0301 basic medicine ,ATPase Inhibitory Protein ,Engineering and technology ,Mitochondrion ,Biochemistry ,Hippocampus ,Mice ,Cognition ,Learning and Memory ,0302 clinical medicine ,Adenosine Triphosphate ,Animal Cells ,Biology (General) ,Energy-Producing Organelles ,Neurons ,chemistry.chemical_classification ,ATP synthase ,biology ,Genetically Modified Organisms ,General Neuroscience ,Brain ,Animal Models ,Mitochondrial Proton-Translocating ATPases ,Biología y Biomedicina / Biología ,Mitochondrial DNA ,Mitochondria ,Cell biology ,Adenosine Diphosphate ,Experimental Organism Systems ,Long Term Memory ,Cellular Structures and Organelles ,Cellular Types ,Anatomy ,Signal transduction ,Genetic Engineering ,General Agricultural and Biological Sciences ,Biotechnology ,Signal Transduction ,Research Article ,Cell signaling ,QH301-705.5 ,Primary Cell Culture ,Mouse Models ,Bioengineering ,Bioenergetics ,Neurotransmission ,General Biochemistry, Genetics and Molecular Biology ,Cell Line ,03 medical and health sciences ,Model Organisms ,Memory ,Reactive Oxygen Metabolite ,Animals ,Molecular Biology Techniques ,Molecular Biology ,Medicine and health sciences ,Reactive oxygen species ,Genetically Modified Animals ,Biology and life sciences ,General Immunology and Microbiology ,Proteins ,Cell Biology ,Metabolism ,Hydrogen Peroxide ,FOS: Engineering and technology ,Mice, Inbred C57BL ,Research and analysis methods ,030104 developmental biology ,chemistry ,Cellular Neuroscience ,Animal Studies ,biology.protein ,Cognitive Science ,Reactive Oxygen Species ,030217 neurology & neurosurgery ,Function (biology) ,Neuroscience ,Cloning - Abstract
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., This study explores the role of ATPase inhibitory factor 1 (IF-1) in neuronal function, revealing that IF-1-mediated changes in ATP synthase modulate the production of mitochondrial reactive oxygen species, and that these changes influence synaptic transmission and cognition.
- Published
- 2021