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.
Highlights
The mitochondrial ATP synthase is the rotatory engine of oxidative phosphorylation (OXPHOS) that utilizes the H+ electrochemical gradient generated by the respiratory chain to synthesize most cellular ATP [1]
To explore the biological role of inhibitory factor 1 (IF1) in neurons, we have developed neuron-specific conditional IF1 knockout (IF1KO) and IF1 overexpressing transgenic (IF1TG) mice
IF1TG transgenic mice were developed by breeding mice harboring human IF1 under the control of a tetracyclineregulated element with mice expressing the transactivator under the control of Calcium/calmodulindependent protein kinase II α (Camk2a) promoter (Fig 1B and 1C)
Summary
The mitochondrial ATP synthase is the rotatory engine of oxidative phosphorylation (OXPHOS) that utilizes the H+ electrochemical gradient generated by the respiratory chain to synthesize most cellular ATP [1]. The ATP synthase is a component required for the efficient execution of cell death [2,3], and recent findings support that it significantly contributes to the permeability transition pore (PTP), which is the mitochondrial. ATPase Inhibitory Factor 1 and neuronal function microarray and proteomic data have been deposited to Gene Expression Omnibus (Project accession: GSE154064) and ProteomeXchange Consortium via the PRIDE partner repository (Project accession: PXD020262), respectively. Remaining relevant data are within the paper and its Supporting Information files
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