Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

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

Mario Pavez-Giani
ORCID logo ,
Pablo Sanchez-Aguilera
,
Nils Bomer
ORCID logo ,
Shigeki Miyamoto
,
Paula Giraldo
,
Silke Oberdorf-Maass
,
Kirsten Nijholt
ORCID logo ,
Salva Yurista
ORCID logo ,
Hendrik Milting
,
Joan Heller Brown
,
Peter Van Der Meer
,
Rudolf A. de Boer
,
Herman H.W. Silljé
,
B. Daan Westenbrink
* ORCID logo
Version 1 : Received: 15 March 2021 / Approved: 26 March 2021 / Online: 26 March 2021 (10:41:00 CET)

A peer-reviewed article of this Preprint also exists.

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.; 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. 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.; 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.

Abstract

Background : ATPase inhibitor 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 extra-mitochondrial glycolysis. Similar perturbations were observed with an IF1 mutant incapable of binding to ATP-synthase (E55A mutation), 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 CaMKII and inhibition of CaMKII or co-expression of catalytically dead CaMKIIδC was sufficient to prevent IF-1 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.

Keywords

mitochondria; Ca2+ handling; heart failure; CaMKII; cardiomyocyte hypertrophy

Subject

Biology and Life Sciences, Biochemistry and Molecular Biology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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