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Nature. 2017 May 4;545(7652):93-97. doi: 10.1038/nature22082. Epub 2017 Apr 26.

The mitochondrial Na+/Ca2+ exchanger is essential for Ca2+ homeostasis and viability.

Author information

1
Center for Translational Medicine, Department of Pharmacology, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA.
2
Cardiovascular Research Center, Department of Physiology, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA.
3
Department of Health and Exercise Physiology, Ursinus College, Collegeville, Pennsylvania 19426, USA.
4
Department of Medicine, University of Minnesota, Minneapolis, Minnesota 55455, USA.
5
Division of Cardiology, Department of Medicine, College of Physicians &Surgeons, Columbia University, New York, New York 10032, USA.
6
Department of Pediatrics, University of Cincinnati, Cincinnati Children's Hospital Medical Center, Howard Hughes Medical Institute, Cincinnati, Ohio 45229, USA.

Abstract

Mitochondrial calcium (mCa2+) has a central role in both metabolic regulation and cell death signalling, however its role in homeostatic function and disease is controversial. Slc8b1 encodes the mitochondrial Na+/Ca2+ exchanger (NCLX), which is proposed to be the primary mechanism for mCa2+ extrusion in excitable cells. Here we show that tamoxifen-induced deletion of Slc8b1 in adult mouse hearts causes sudden death, with less than 13% of affected mice surviving after 14 days. Lethality correlated with severe myocardial dysfunction and fulminant heart failure. Mechanistically, cardiac pathology was attributed to mCa2+ overload driving increased generation of superoxide and necrotic cell death, which was rescued by genetic inhibition of mitochondrial permeability transition pore activation. Corroborating these findings, overexpression of NCLX in the mouse heart by conditional transgenesis had the beneficial effect of augmenting mCa2+ clearance, preventing permeability transition and protecting against ischaemia-induced cardiomyocyte necrosis and heart failure. These results demonstrate the essential nature of mCa2+ efflux in cellular function and suggest that augmenting mCa2+ efflux may be a viable therapeutic strategy in disease.

PMID:
28445457
PMCID:
PMC5731245
DOI:
10.1038/nature22082
[Indexed for MEDLINE]
Free PMC Article

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