PKA Phosphorylates the ATPase Inhibitory Factor 1 and Inactivates Its Capacity to Bind and Inhibit the Mitochondrial H+-ATP Synthase

Background: During the development of heart failure cardiac fuel metabolism switches from predominantly fatty acid oxidation (FAO) to increased reliance on glucose, especially glycolysis. Mechanisms responsible for the switch are poorly understood but appear to be coupled with impaired mitochondrial function. We recently demonstrated that increased glucose metabolism is required for cardiomyocytes growth during pathological remodeling. Hypothesis: Upregulation of mitochondrial ATPase inhibitory factor 1 (ATPIF1) in hypertrophied hearts suppresses ATP synthesis and shifts cardiac metabolism from fatty acid oxidation towards glucose metabolism. Methods and Results: We report that ATPIF1 expression is upregulated in cardiomyocytes and mouse hearts undergoing pathological hypertrophy. Using genetic models of ATPIF1 gain- and loss-of-function in cardiomyocytes and in mouse hearts,we find that upregulation of ATPIF1 in cardiac hypertrophy inhibits ATP synthesis. Furthermore, quantitative analysis of chemical crosslinking by mass spectrometry revealed that increased expression of ATPIF1 promoted the formation of F o F 1 -ATP synthase nonproductive tetramer. Impairment of F o F 1 -ATP synthase function in respiring mitochondria increasedROS generation resulting in transcriptional activation of glycolysis. Cardiac-specific deletion of ATPIF1 in mice prevented the switch to glycolysis in pressure overload induced cardiac hypertrophy. Conclusions: We show that upregulation of ATPIF1 drives glucose metabolism at the expense of energy supply during the pathological growth of cardiomyocytes. Our study proposes a central role of ATP synthase in toggling anabolic and catabolic metabolism during pathological remodeling, illustrating a new concept for metabolic reprogramming of the heart.

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Up-regulation of the ATPase Inhibitory Factor 1 (IF1) of the Mitochondrial H+-ATP Synthase in Human Tumors Mediates the Metabolic Shift of Cancer Cells to a Warburg Phenotype

Journal of Biological Chemistry ◽

10.1074/jbc.m110.146480 ◽

2010 ◽

Vol 285 (33) ◽

pp. 25308-25313 ◽

Cited By ~ 128

Author(s):

Laura Sánchez-Cenizo ◽

Laura Formentini ◽

Marcos Aldea ◽

Álvaro D. Ortega ◽

Paula García-Huerta ◽

...

Keyword(s):

Cancer Cells ◽

Atp Synthase ◽

Human Tumors ◽

Inhibitory Factor ◽

Metabolic Shift ◽

Inhibitory Factor 1

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Faculty Opinions recommendation of F1F0-ATP Synthase Inhibitory Factor 1 in the Normal Pancreas and in Pancreatic Ductal Adenocarcinoma: Effects on Bioenergetics, Invasion and Proliferation.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.733703416.793549717 ◽

2018 ◽

Author(s):

Silvana Curci ◽

Matilde Colella

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Atp Synthase ◽

Inhibitory Factor ◽

Ductal Adenocarcinoma ◽

Normal Pancreas ◽

F1f0 Atp Synthase ◽

Inhibitory Factor 1

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Generation of mitochondrial reactive oxygen species is controlled by ATPase inhibitory factor 1 and regulates cognition

PLoS Biology ◽

10.1371/journal.pbio.3001252 ◽

2021 ◽

Vol 19 (5) ◽

pp. e3001252

Author(s):

Pau B. Esparza-Moltó ◽

Inés Romero-Carramiñana ◽

Cristina Núñez de Arenas ◽

Marta P. Pereira ◽

Noelia Blanco ◽

...

Keyword(s):

Reactive Oxygen Species ◽

Synaptic Transmission ◽

Atp Synthase ◽

Reactive Oxygen ◽

Synaptic Function ◽

Inhibitory Factor ◽

Oxygen Species ◽

Mitochondrial Reactive Oxygen Species ◽

Mitochondrial Atp Synthase ◽

Inhibitory Factor 1

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.

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The potential role of mitochondrial ATP synthase inhibitory factor 1 (IF1) in coronary heart disease: a literature review

Lipids in Health and Disease ◽

10.1186/s12944-017-0430-9 ◽

2017 ◽

Vol 16 (1) ◽

Cited By ~ 4

Author(s):

Serban Maierean ◽

Maria-Corina Serban ◽

Manfredi Rizzo ◽

Giuseppe Lippi ◽

Amirhossein Sahebkar ◽

...

Keyword(s):

Coronary Heart Disease ◽

Heart Disease ◽

Literature Review ◽

Atp Synthase ◽

Potential Role ◽

Inhibitory Factor ◽

Mitochondrial Atp Synthase ◽

Inhibitory Factor 1

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ATPase Inhibitory Factor-1 Disrupts Mitochondrial Ca2+ Handling and Promotes Pathological Cardiac Hypertrophy through CaMKIIδ

International Journal of Molecular Sciences ◽

10.3390/ijms22094427 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4427

Author(s):

Mario G. Pavez-Giani ◽

Pablo I. Sánchez-Aguilera ◽

Nils Bomer ◽

Shigeki Miyamoto ◽

Harmen G. Booij ◽

...

Keyword(s):

Atp Synthase ◽

Inhibitory Factor ◽

Wild Type ◽

Mitochondrial Fragmentation ◽

Mitochondrial Oxidative Stress ◽

Pathological Cardiac Hypertrophy ◽

Calmodulin Kinase ◽

Pathological Hypertrophy ◽

Metabolic Remodeling ◽

Inhibitory Factor 1

ATPase inhibitory factor-1 (IF1) preserves cellular ATP under conditions of respiratory collapse, yet the function of IF1 under normal respiring conditions is unresolved. We tested the hypothesis that IF1 promotes mitochondrial dysfunction and pathological cardiomyocyte hyper-trophy in the context of heart failure (HF). Methods and results: Cardiac expression of IF1 was increased in mice and in humans with HF, downstream of neurohumoral signaling pathways and in patterns that resembled the fetal-like gene program. Adenoviral expression of wild-type IF1 in primary cardiomyocytes resulted in pathological hypertrophy and metabolic remodeling as evi-denced by enhanced mitochondrial oxidative stress, reduced mitochondrial respiratory capacity, and the augmentation of extramitochondrial glycolysis. Similar perturbations were observed with an IF1 mutant incapable of binding to ATP synthase (E55A mutation), an indication that these ef-fects occurred independent of binding to ATP synthase. Instead, IF1 promoted mitochondrial fragmentation and compromised mitochondrial Ca2+ handling, which resulted in sarcoplasmic re-ticulum Ca2+ overloading. The effects of IF1 on Ca2+ handling were associated with the cytosolic activation of calcium–calmodulin kinase II (CaMKII) and inhibition of CaMKII or co-expression of catalytically dead CaMKIIδC was sufficient to prevent IF1 induced pathological hypertrophy. Conclusions: IF1 represents a novel member of the fetal-like gene program that contributes to mi-tochondrial dysfunction and pathological cardiac remodeling in HF. Furthermore, we present ev-idence for a novel, ATP-synthase-independent, role for IF1 in mitochondrial Ca2+ handling and mitochondrial-to-nuclear crosstalk involving CaMKII.

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