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Upregulation of mitochondrial ATPase inhibitory factor 1 (ATPIF1) mediates increased glycolysis in mouse hearts
- Source :
- Journal of Clinical Investigation. May 15, 2022, Vol. 132 Issue 10
- Publication Year :
- 2022
-
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 [F.sub.0][F.sub.1]-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 [alpha]-adrenergic stimulation. Chemical cross-linking mass spectrometry analysis of hearts hypertrophied by pressure overload suggested that increased expression of ATPIF1 promoted the formation of [F.sub.o][F.sub.1]-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 [HIF1.sub.[alpha]], 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 [F.sub.o][F.sub.1]-ATP synthase a critical role in metabolic rewiring during the pathological remodeling of the heart.<br />Introduction Mitochondrial [F.sub.o][F.sub.1]-ATP synthase, or complex V, is composed of a soluble catalytic [F.sub.1] region (main subunit composition [[alpha].sub.3][[beta].sub.3][gamma]) in the mitochondrial matrix and a membrane-embedded [F.sub.o] region (1). The [...]
- Subjects :
- Heart attack -- Complications and side effects -- Genetic aspects
Gene expression -- Research
Adenosine triphosphatase -- Health aspects -- Physiological aspects -- Genetic aspects
Cardiovascular research
Mitochondria -- Health aspects -- Physiological aspects -- Genetic aspects
Heart enlargement -- Development and progression -- Genetic aspects
Glycolysis -- Research
Health care industry
Subjects
Details
- Language :
- English
- ISSN :
- 00219738
- Volume :
- 132
- Issue :
- 10
- Database :
- Gale General OneFile
- Journal :
- Journal of Clinical Investigation
- Publication Type :
- Academic Journal
- Accession number :
- edsgcl.704807481
- Full Text :
- https://doi.org/10.1172/JCI155333