The Journal of Clinical Investigation - Upregulation of mitochondrial ATPase inhibitory factor 1 (ATPIF1) mediates increased glycolysis in mouse hearts

Sep 4, 2026

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Pathological cardiac hypertrophy and chronic stress reprogram cardiac fuel metabolism toward glucose utilization, particularly glycolysis, while diminishing ATP production; the molecular basis of this shift remains unclear. This study identifies mitochondrial ATPase inhibitory factor 1 (ATPIF1) as a stress-upregulated protein in mouse hearts. ATPIF1 promotes formation of FoF1-ATP synthase nonproductive tetramers, stalls electron flow, induces mitochondrial ROS, stabilizes HIF1α, and activates glycolytic transcription. Cardiac-specific ATPIF1 deletion prevents the metabolic switch and protects against pathological remodeling.

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CategoryResearch & Report

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Introduction

Mitochondrial FoF1-ATP synthase and ATPIF1 regulation

ATPIF1 function in hypertrophic hearts

The Journal of Clinical Investigation RESEAR CH ARTICLE Upregulation of mitochondrial ATPase inhibitory factor 1 (ATPIF1) mediates increased glycolysis in mouse hearts Bo Zhou,1 Arianne Caudal,1 Xiaoting Tang,2 Juan D. Chavez,2 Timothy S. McMillen,1 Andrew Keller,2 Outi Villet,1 Mingyue Zhao,1 Yaxin Liu,1 Julia Ritterhoff,1 Pei Wang,1 Stephen C. Kolwicz Jr.,1 Wang Wang,1 James E. Bruce,2 and Rong Tian1 1Mitochondria and Metabolism Center, Department of Anesthesiology &Pain Medicine, and 2Department of Genome Sciences, University of Washington, Seattle, Washington, USA. In hypertrophied and failing hearts, fuel metabolism is reprogrammed to increase glucose metabolism, especially glycolysis. This metabolic shift favors biosynthetic function at the expense of ATP production. Mechanisms responsible for the switch are poorly understood. We found that inhibitory factor 1 of the mitochondrial FoF1-ATP synthase (ATPIF1), a protein known to inhibit ATP hydrolysis by the reverse function of ATP synthase during ischemia, was significantly upregulated in pathological cardiac hypertrophy induced by pressure overload, myocardial infarction, or α-adrenergic stimulation. Chemical cross-linking mass spectrometry analysis of hearts hypertrophied by pressure overload suggested that increased expression of ATPIF1 promoted the formation of FoF1-ATP synthase nonproductive tetramer. Using ATPIF1 gain-and loss-of-function cell models, we demonstrated that stalled electron flow due to impaired ATP synthase activity triggered mitochondrial ROS generation, which stabilized HIF1α, leading to transcriptional activation of glycolysis. Cardiacspecific deletion of ATPIF1 in mice prevented the metabolic switch and protected against the pathological remodeling during chronic stress. These results uncover a function of ATPIF1 in nonischemic hearts, which gives FoF1-ATP synthase a critical role in metabolic rewiring during the pathological remodeling of the heart. Introduction Mitochondrial FoF1-ATP synthase, or complex V, is composed of a soluble catalytic F1 region (main subunit composition α3β3γ) in the mitochondrial matrix and a membrane-embedded Fo region (1) . The enzyme complex catalyzes ATP synthesis using the mitochondrial proton gradient generated by the electron transport chain (1). When the proton gradient is compromised, FoF1-ATP synthase reverses its function from ATP synthesis to ATP hydrolysis so that protons can be pumped into the intermembrane space. Such a response would sustain mitochondrial membrane potential at the expense of cellular ATP level. On the other hand, the reduced proton gradient results in matrix pH acidification, which promotes binding of ATPase inhibitory factor 1 (ATPIF1), a 12 kDa protein molecule, to the F1 region of FoF1-ATP synthase to inhibit its activity, thus slowing ATP hydrolysis (2). Under normal conditions, ATPIF1 was thought not to interact with complex V, thus leaving its ATP synthesis function unaffected. Consistent with this notion, a previous study showed that whole-body deletion of ATPIF1 caused no obvious phenotype in unstressed mice (3). Our recent studies using cross-linking mass spectrometry have revealed that ATPIF1 exists proximal to the α and β catalytic subunits of F1-ATPase in respiring mitochondria, suggesting that Conflict of interest: The authors have declared that no conflict of interest exists. Copyright: © 2022, Zhou et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License. Submitted: September 27, 2021; Accepted: April 1, 2022; Published: May 16, 2022. Reference information: J Clin Invest. 2022;132(10):e155333 . [https://doi.org/10.1172/JCI155333](https://doi.org/10.1172/JCI155333) . ATPIF1 could interact with complex V in ATP synthesis mode (4, 5). In several cancer cell lines, increased expression of ATPIF1 is linked to reduced oxidative phosphorylation (OXPHOS) and increased glycolysis (6). Furthe

FAQs

What triggers the upregulation of ATPIF1 during pathological cardiac hypertrophy?

ATPIF1 is significantly upregulated in pathological cardiac hypertrophy induced by pressure overload, myocardial infarction, or α-adrenergic stimulation.

How does ATPIF1 promote increased glycolysis?

ATPIF1 upregulation increases formation of FoF1-ATP synthase nonproductive tetramers, which impairs ATP synthesis, causes stalled electron flow and mitochondrial ROS generation, stabilizing HIF1α and activating glycolysis transcription.

What is the effect of cardiac-specific ATPIF1 deletion in mice?

Cardiacspecific deletion of ATPIF1 prevents the metabolic switch and protects against pathological remodeling during chronic stress.

Sep 4, 2026

Uploaded by Paura