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Article

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

1
Department of Cardiology, University Medical Center Groningen, University of Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands
2
Department of Pharmacology, University of California San Diego, San Diego, CA 92093, USA
3
Erich and Hanna Klessmann Institute, Heart and Diabetes Center NRW, University Hospital of the Ruhr-University Bochum, Georgstrasse 11, 32545 Bad Oeynhausen, Germany
*
Author to whom correspondence should be addressed.
These authors contributed equally.
Academic Editor: Darío Acuña-Castroviejo
Int. J. Mol. Sci. 2021, 22(9), 4427; https://doi.org/10.3390/ijms22094427
Received: 15 March 2021 / Revised: 10 April 2021 / Accepted: 13 April 2021 / Published: 23 April 2021
(This article belongs to the Special Issue Mitochondrial Control of Muscle Growth in Health and Diseases)
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 hypertrophy 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 evidenced 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 effects occurred independent of binding to ATP synthase. Instead, IF1 promoted mitochondrial fragmentation and compromised mitochondrial Ca2+ handling, which resulted in sarcoplasmic reticulum 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 mitochondrial dysfunction and pathological cardiac remodeling in HF. Furthermore, we present evidence for a novel, ATP-synthase-independent, role for IF1 in mitochondrial Ca2+ handling and mitochondrial-to-nuclear crosstalk involving CaMKII. View Full-Text
Keywords: mitochondria; calcium handling; heart failure; CaMKII; cardiomyocyte hypertrophy mitochondria; calcium handling; heart failure; CaMKII; cardiomyocyte hypertrophy
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MDPI and ACS Style

Pavez-Giani, M.G.; Sánchez-Aguilera, P.I.; Bomer, N.; Miyamoto, S.; Booij, H.G.; Giraldo, P.; Oberdorf-Maass, S.U.; Nijholt, K.T.; Yurista, S.R.; Milting, H.; van der Meer, P.; Boer, R.A.d.; Heller Brown, J.; Sillje, H.W.H.; Westenbrink, B.D. ATPase Inhibitory Factor-1 Disrupts Mitochondrial Ca2+ Handling and Promotes Pathological Cardiac Hypertrophy through CaMKIIδ. Int. J. Mol. Sci. 2021, 22, 4427. https://doi.org/10.3390/ijms22094427

AMA Style

Pavez-Giani MG, Sánchez-Aguilera PI, Bomer N, Miyamoto S, Booij HG, Giraldo P, Oberdorf-Maass SU, Nijholt KT, Yurista SR, Milting H, van der Meer P, Boer RAd, Heller Brown J, Sillje HWH, Westenbrink BD. ATPase Inhibitory Factor-1 Disrupts Mitochondrial Ca2+ Handling and Promotes Pathological Cardiac Hypertrophy through CaMKIIδ. International Journal of Molecular Sciences. 2021; 22(9):4427. https://doi.org/10.3390/ijms22094427

Chicago/Turabian Style

Pavez-Giani, Mario G., Pablo I. Sánchez-Aguilera, Nils Bomer, Shigeki Miyamoto, Harmen G. Booij, Paula Giraldo, Silke U. Oberdorf-Maass, Kirsten T. Nijholt, Salva R. Yurista, Hendrik Milting, Peter van der Meer, Rudolf A. de Boer, Joan Heller Brown, Herman W. H. Sillje, and B. Daan Westenbrink. 2021. "ATPase Inhibitory Factor-1 Disrupts Mitochondrial Ca2+ Handling and Promotes Pathological Cardiac Hypertrophy through CaMKIIδ" International Journal of Molecular Sciences 22, no. 9: 4427. https://doi.org/10.3390/ijms22094427

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