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

Author

Listed:
  • Timothy S. Luongo

    (Center for Translational Medicine, Temple University School of Medicine)

  • Jonathan P. Lambert

    (Center for Translational Medicine, Temple University School of Medicine)

  • Polina Gross

    (Cardiovascular Research Center, Temple University School of Medicine)

  • Mary Nwokedi

    (Center for Translational Medicine, Temple University School of Medicine)

  • Alyssa A. Lombardi

    (Center for Translational Medicine, Temple University School of Medicine)

  • Santhanam Shanmughapriya

    (Center for Translational Medicine, Temple University School of Medicine)

  • April C. Carpenter

    (Ursinus College)

  • Devin Kolmetzky

    (Center for Translational Medicine, Temple University School of Medicine)

  • Erhe Gao

    (Center for Translational Medicine, Temple University School of Medicine)

  • Jop H. van Berlo

    (University of Minnesota)

  • Emily J. Tsai

    (College of Physicians & Surgeons, Columbia University)

  • Jeffery D. Molkentin

    (University of Cincinnati, Cincinnati Children’s Hospital Medical Center, Howard Hughes Medical Institute)

  • Xiongwen Chen

    (Cardiovascular Research Center, Temple University School of Medicine)

  • Muniswamy Madesh

    (Center for Translational Medicine, Temple University School of Medicine)

  • Steven R. Houser

    (Cardiovascular Research Center, Temple University School of Medicine)

  • John W. Elrod

    (Center for Translational Medicine, Temple University School of Medicine)

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.

Suggested Citation

  • Timothy S. Luongo & Jonathan P. Lambert & Polina Gross & Mary Nwokedi & Alyssa A. Lombardi & Santhanam Shanmughapriya & April C. Carpenter & Devin Kolmetzky & Erhe Gao & Jop H. van Berlo & Emily J. Ts, 2017. "The mitochondrial Na+/Ca2+ exchanger is essential for Ca2+ homeostasis and viability," Nature, Nature, vol. 545(7652), pages 93-97, May.
    • Handle: RePEc:nat:nature:v:545:y:2017:i:7652:d:10.1038_nature22082
    DOI: 10.1038/nature22082
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    Cited by:

    1. Masataka Kawamura & Catherine Parmentier & Samrat Ray & Sergi Clotet-Freixas & Sharon Leung & Rohan John & Laura Mazilescu & Emmanuel Nogueira & Yuki Noguchi & Toru Goto & Bhranavi Arulratnam & Sujani, 2024. "Normothermic ex vivo kidney perfusion preserves mitochondrial and graft function after warm ischemia and is further enhanced by AP39," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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