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 controversial1. Slc8b1 encodes the mitochondrial Na+/Ca2+ exchanger (NCLX), which is proposed to be the primary mechanism for mCa2+ extrusion in excitable cells2,3. 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.

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Acknowledgements

We thank T. Tierney, N. Shah, and P. Kelly for technical assistance in the Elrod Laboratory. We thank S. Modla for her expertise in TEM sample processing (Delaware Biotechnology Institute). This study was supported by grants to J.W.E. from the NIH (R01 HL123966, P01 DA037830 sub-8614) and AHA (14SDG18910041) and (15PRE25080299 to T.S.L.), (16PRE31030038 to A.A.L.), and (17PRE33460423 to J.P.L.).

Author information

Affiliations

  1. Center for Translational Medicine, Department of Pharmacology, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA

    • Timothy S. Luongo
    • , Jonathan P. Lambert
    • , Mary Nwokedi
    • , Alyssa A. Lombardi
    • , Santhanam Shanmughapriya
    • , Devin Kolmetzky
    • , Erhe Gao
    • , Muniswamy Madesh
    •  & John W. Elrod
  2. Cardiovascular Research Center, Department of Physiology, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA

    • Polina Gross
    • , Xiongwen Chen
    •  & Steven R. Houser
  3. Department of Health and Exercise Physiology, Ursinus College, Collegeville, Pennsylvania 19426, USA

    • April C. Carpenter
  4. Department of Medicine, University of Minnesota, Minneapolis, Minnesota 55455, USA

    • Jop H. van Berlo
  5. Division of Cardiology, Department of Medicine, College of Physicians & Surgeons, Columbia University, New York, New York 10032, USA

    • Emily J. Tsai
  6. Department of Pediatrics, University of Cincinnati, Cincinnati Children’s Hospital Medical Center, Howard Hughes Medical Institute, Cincinnati, Ohio 45229, USA

    • Jeffery D. Molkentin

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Contributions

J.W.E. and T.S.L. contributed to study design, data analysis and writing the paper; T.S.L. was involved with all assays and data collection; J.P.L. performed western blots and NADH assays; P.G. performed ACM iCa2+ transient analysis; M.N. performed myocardial infarction data acquisition; A.A.L. assisted with the ischaemia reperfusion study and mitochondrial membrane potential assays; S.S. and M.M. assisted with efflux analysis in permeabilized cells; A.C.C. performed qPCR assays; D.K. performed histology; E.G. performed ischaemia reperfusion and myocardial infarction surgeries; J.H.v.B. and J.D.M. aided mutant mouse generation; E.J.T. supplied human heart samples; X.C. performed radiotelemeter implantation and assisted with electrocardiogram analysis; J.W.E., J.H.v.B, T.S.L., S.R.H., J.P.L., A.C.C. and A.A.L. assisted with data interpretation and edited the manuscript.

Corresponding author

Correspondence to John W. Elrod.

Reviewer Information: Nature thanks M. Murphy and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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    This file contains Supplementary Figure 1, the uncropped blots and band density results.

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https://doi.org/10.1038/nature22082

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