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J Physiol. 2019 Feb 16. doi: 10.1113/JP276766. [Epub ahead of print]

CaMKII Does not Control Mitochondrial Ca2+ Uptake in Cardiac Myocytes.

Author information

1
Comprehensive Heart Failure Center (CHFC), University Clinic Würzburg, 97078, Würzburg, Germany.
2
Affiliation when/at which experiments were performed: Clinic III for Internal Medicine, University Clinic Homburg, 66421, Homburg, Germany.
3
Current address: Institute for Molecular Cell Biology, University of the Saarland, 66421, Homburg, Germany.
4
Institute of Experimental Cardiology, Heidelberg University Hospital, Heidelberg, Germany.
5
German Center for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim, Germany.
6
Department of Cardiology, Heidelberg University Hospital, Heidelberg, Germany.
7
Department of Biophysics, CIPMM, School of Medicine, University of the Saarland, 66421, Homburg, Germany.

Abstract

KEY POINTS:

Mitochondrial Ca2+ uptake stimulates the Krebs cycle to regenerate the reduced forms of pyridine nucleotides (NADH, NADPH and FADH2 ) required for ATP production and ROS elimination. It was previously proposed that Ca2+ /calmodulin-dependent protein kinase II (CaMKII) regulates mitochondrial Ca2+ uptake via MCU phosphorylation. We used two mouse models with either global deletion of CaMKIIδ (CaMKIIδ KO) or cardiomyocyte-specific deletion of CaMKIIδ and γ (CaMKIIδ/γ DKO) to interrogate whether CaMKII controls mitochondrial Ca2+ uptake in isolated mitochondria and during β-adrenergic stimulation in cardiac myocytes. CaMKIIδ/γ controlled neither Ca2+ uptake, respiration nor ROS emission in isolated cardiac mitochondria nor in isolated cardiac myocytes during β-adrenergic stimulation and pacing. Our results argue against a relevant role of CaMKII for mitochondrial Ca2+ uptake in cardiac myocytes under physiological conditions.

ABSTRACT:

Mitochondria are the main source of ATP and reactive oxygen species (ROS) in cardiac myocytes. Furthermore, activation of the mitochondrial permeability transition pore (mPTP) induces programmed cell death. These processes are essentially controlled by Ca2+ , which is taken up into mitochondria via the Ca2+ uniporter (MCU). It was recently proposed that Ca2+ /calmodulin-dependent protein kinase II (CaMKII) regulates Ca2+ uptake by interacting with the MCU, thereby affecting mPTP activation and programmed cell death. Here, we addressed the role of CaMKII under physiological conditions in which mitochondrial Ca2+ uptake matches energy supply to demand of cardiac myocytes. To this end, we measured mitochondrial Ca2+ uptake in isolated mitochondria and cardiac myocytes harvested from cardiomyocyte-specific CaMKII δ and γ double KO (CaMKIIδ/γ DKO) and global CaMKIIδ KO mice. To simulate a physiological workload increase, cardiac myocytes were subjected to β-adrenergic stimulation (by isoproterenol superfusion) and increase in stimulation frequency (from 0.5 to 5 Hz). No differences in mitochondrial Ca2+ accumulation were detected in isolated mitochondria or cardiac myocytes from both CaMKII KO models compared with wild-type (WT) littermates. Mitochondrial redox state and ROS production were unchanged in CaMKIIδ/γ DKO, whereas we observed a mild oxidation of mitochondrial redox state and an increase in H2 O2 emission from CaMKIIδ KO cardiac myocytes exposed to an increase in workload. In conclusion, our results argue against a relevant regulation of mitochondrial Ca2+ uptake via the MCU or mPTP activation by CaMKII in cardiac myocytes under physiological conditions. This article is protected by copyright. All rights reserved.

PMID:
30770570
DOI:
10.1113/JP276766

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