Upregulation of mitochondrial ATPase inhibitory factor 1 (ATPIF1) mediates increased glycolysis in mouse hearts
Bo Zhou, … , James E. Bruce, Rong Tian
Bo Zhou, … , James E. Bruce, Rong Tian
Published May 16, 2022
Citation Information: J Clin Invest. 2022;132(10):e155333. https://doi.org/10.1172/JCI155333.
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Research Article Cardiology Metabolism

Upregulation of mitochondrial ATPase inhibitory factor 1 (ATPIF1) mediates increased glycolysis in mouse hearts

Abstract

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. Cardiac-specific 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.

Authors

Bo Zhou, Arianne Caudal, Xiaoting Tang, Juan D. Chavez, Timothy S. McMillen, Andrew Keller, Outi Villet, Mingyue Zhao, Yaxin Liu, Julia Ritterhoff, Pei Wang, Stephen C. Kolwicz Jr., Wang Wang, James E. Bruce, Rong Tian

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Figure 1

ATPIF1 was upregulated in pathological cardiac hypertrophy.

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ATPIF1 was upregulated in pathological cardiac hypertrophy. (A–E) ATPIF1...
(A–E) ATPIF1 protein levels were assayed in cardiac mitochondria isolated from mice subjected to TAC (A, n = 5), left anterior descending artery ligation (MI; B, n = 4), or sham operations (n = 4–7) for 28 days; in primary adult rat cardiomyocytes treated with 10 μM PE for 48 hours (C, n = 6); in isolated cardiomyocytes from mice subjected to TAC or sham surgery for 28 days (E, n = 4); and in cardiac tissue lysates prepared from mice subjected to a motorized treadmill 5 times per week for 10 weeks to induce physiological hypertrophy (D, n = 6). (F) Densitometric analysis of ATPIF1 protein levels from each group by ImageJ. (G) Schematic of putative c-fos/c-Jun binding sites in mouse ATPIF1 promoter. The predicted binding sites are in the regions of –586/–579 bp, –256/–250 bp, and –235/–228 bp, respectively. Truncated promoter fragments containing decreasing numbers of the binding sites are indicated. (H and I) Promoter activity in primary adult rat cardiomyocytes carrying dual-luciferase reporters fused with mouse ATPIF1 promoter sequence. Treatment with or without 20 μM T-5224 (AP-1 activity inhibitor) or 10 μM PE is indicated [NS vs. P(–928/–1 bp), n = 4]. (J) ATPIF1 mRNA expression in adult rat cardiomyocytes receiving indicated treatment (NS vs. vehicle treated with DMSO, n = 4). Data are means ± SEM of the values. P values were determined using unpaired 2-tailed Student’s t test comparing the treatment group with its respective controls (F and H), 1-way ANOVA followed by Dunnett’s multiple-comparison test (I), or 2-way ANOVA followed by Tukey’s multiple-comparison test (J); *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.