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

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. Tsai, Jeffery D. Molkentin, Xiongwen Chen, Muniswamy Madesh, Steven R. Houser and John W. Elrod ()
Additional contact information
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

Nature, 2017, vol. 545, issue 7652, 93-97

Abstract: 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.

Date: 2017
References: Add references at CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/nature22082 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:545:y:2017:i:7652:d:10.1038_nature22082

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/nature22082

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().