Regulation of the H+-ATP synthase by IF1: a role in mitohormesis

Abstract

The mitochondrial H+-ATP synthase is a primary hub of cellular homeostasis by providing the energy required to sustain cellular activity and regulating the production of signaling molecules that reprogram nuclear activity needed for adaption to changing cues. Herein, we summarize findings regarding the regulation of the activity of the H+-ATP synthase by its physiological inhibitor, the ATPase inhibitory factor 1 (IF1) and their functional role in cellular homeostasis. First, we outline the structure and the main molecular mechanisms that regulate the activity of the enzyme. Next, we describe the molecular biology of IF1 and summarize the regulation of IF1 expression and activity as an inhibitor of the H+-ATP synthase emphasizing the role of IF1 as a main driver of energy rewiring and cellular signaling in cancer. Findings in transgenic mice in vivo indicate that the overexpression of IF1 is sufficient to reprogram energy metabolism to an enhanced glycolysis and activate reactive oxygen species (ROS)-dependent signaling pathways that promote cell survival. These findings are placed in the context of mitohormesis, a program in which a mild mitochondrial stress triggers adaptive cytoprotective mechanisms that improve lifespan. In this regard, we emphasize the role played by the H+-ATP synthase in modulating signaling pathways that activate the mitohormetic response, namely ATP, ROS and target of rapamycin (TOR). Overall, we aim to highlight the relevant role of the H+-ATP synthase and of IF1 in cellular physiology and the need of additional studies to decipher their contributions to aging and age-related diseases.

Alternative oxidase confers nutritional limitation on Drosophila development

“…The depletion of respiratory substrates, as observed in larvae cultured on low‐nutrient medium, should logically lead to the opposite outcome, that is, to the respiratory‐chain electron carriers becoming completely oxidized. However, respiratory chain shutdown might occur under such circumstances via the complex V inhibitor IF1 (Esparza‐Moltó, Nuevo‐Tapioles, & Cuezva, ), creating the conditions for AOX activation. AOX activation could, in principle, result from a number of metabolic consequences of low‐nutrient diet that are hard to predict, given that rather little is known about the nutrients (other than triglycerides) that are stored in the pupa.…”

Decrement in resting and insulin‐stimulated soleus muscle mitochondrial respiration is an early event in diet‐induced obesity in mice

“…Moreover, it was shown that obese and T2DM patients present an increased activity of inhibitory factor 1 (IF‐1) in the mitochondrial matrix (Formentini et al., ). Inhibitory factor 1 is known to reduce the activity of ATP synthases, leading to a higher Δ p and electron leakage (Esparza‐Moltó, Nuevo‐Tapioles, & Cuezva, ). Therefore, other mechanisms might be playing important roles and affecting the results obtained here.…”

Tissue‐specific expression and post‐transcriptional regulation of the ATPase inhibitory factor 1 (IF1) in human and mouse tissues

“…IF1 is consistently found to be dephosphorylated in hypoxic cells (6). Moreover, IF1 is highly overexpressed in cancer cell lines (8) and in prevalent human carcinomas (3,9), where it is found largely in its active dephosphorylated state (6). Because of the IF1-mediated inhibition of the ATP synthetic activity of the enzyme (6,8), the overexpression of IF1 in human carcinomas (3,9) and mesenchymal stem cells (10) has been shown to play a relevant role in triggering the metabolic reprogramming of the cells to an enhanced glycolytic flux.…”

“…The inhibitor protein is encoded in the ATP5IF1 gene, which is located in chromosomes 1 and 4 in the human and mouse genomes, respectively. IF1 is a small, intrinsically disordered protein (2,3) that reversibly binds to the enzyme (4), inhibiting its ATP synthetic and hydrolytic activities, depending on cellular conditions (1,5). Phosphorylation of conserved S39 in human IF1 prevents its binding to the enzyme, and thus blocks its activity as an inhibitor of ATP synthase (6).…”

“…Moreover, IF1 is highly overexpressed in cancer cell lines (8) and in prevalent human carcinomas (3,9), where it is found largely in its active dephosphorylated state (6). Because of the IF1-mediated inhibition of the ATP synthetic activity of the enzyme (6,8), the overexpression of IF1 in human carcinomas (3,9) and mesenchymal stem cells (10) has been shown to play a relevant role in triggering the metabolic reprogramming of the cells to an enhanced glycolytic flux. In agreement with these findings, conditional tissue-specific overexpression of IF1 (11) or of an active mutant version of the protein (12,13) in different mouse tissues triggers metabolic reprograming of the targeted tissues to an enhanced glycolysis.…”