The mitochondrial Na+/Ca2+ exchanger is essential for Ca2+ homeostasis and viability
Open accessAbstract
Mitochondrial calcium (m Ca 2+) 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+/Ca 2+ exchanger (NCLX), which is proposed to be the primary mechanism for m Ca 2+ 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 m Ca 2+ 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 m Ca 2+ clearance, preventing permeability transition and protecting against ischaemia-induced cardiomyocyte necrosis and heart failure. These results demonstrate the essential nature of m Ca 2+ efflux in cellular function and suggest that augmenting m Ca 2+ efflux may be a viable therapeutic strategy in disease.
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Inducible cardiomyocyte-specific deletion of Slc8b1 in mice provokes sudden lethality owing to heart failure imposed by MTP-regulated necrosis upon mitochondrial Ca2+ overload.
“Moreover, the inducible cardiomyocyte-specific deletion of solute carrier family 8 member B1 (Slc8b1, which encodes a mitochondrial potassium-dependent sodium/calcium exchanger) in mice reportedly provokes sudden lethality owing to heart failure imposed by MTP-regulated necrosis upon mitochondrial Ca2+ overload [420].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [420]
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- Authors
- Luongo, T. S., Lambert, J. P., Gross, P., Nwokedi, M., Lombardi, A. A., Shanmughapriya, S., Carpenter, A. C., Kolmetzky, D., Gao, E., van Berlo, J. H., Tsai, E. J., Molkentin, J. D., Chen, X., Madesh, M., Houser, S. R., & Elrod, J. W.
- Affiliations
- Temple University (US)
- Ursinus College (US)
- Columbia University (US)
- Cincinnati Children's Hospital Medical Center (US)
- Corresponding author
- Elrod, John W.
- ORCID
- Venue
- Nature
- Published
- 2017-04-26
- Volume
- 545
- Issue
- 7652
- Pages
- 93-97
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5731245
- OpenAlex
- W2609751917
- Cited by
- 396
- References
- 39
- Citations by year
- 2026: 29 · 2025: 39 · 2024: 33 · 2023: 41 · 2022: 48 · 2021: 53 · 2020: 70 · 2019: 35 · 2018: 35 · 2017: 13
- FWCI
- 17.09
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institutes of Health (1k08hl109159-01a1)
- National Heart, Lung, and Blood Institute (K08-HL109159, R01HL123966, R01HL136954, R01HL132831, R01HL086699, R01HL130072)
- National Institute on Drug Abuse (P01DA037830)
- National Institute of General Medical Sciences (R01GM109882)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Keywords
- mitochondrial Na+/Ca2+ exchanger, NCLX, mitochondrial calcium homeostasis, mitochondrial calcium overload, sudden cardiac death, heart failure, cardiac dysfunction, ischemia-reperfusion injury, myocardial necrosis, mitochondrial permeability transition pore, superoxide production, cardioprotection
- MeSH terms
- Mitochondrial Permeability Transition Pore, Animals, Calcium, Cell Survival, Death, Sudden, Female, Heart Failure, HeLa Cells, Homeostasis, Humans, Male, Mitochondria, Myocardium, Necrosis, Superoxides, Tamoxifen, Reperfusion Injury, Gene Deletion, Sodium-Calcium Exchanger, Ventricular Remodeling, Myocytes, Cardiac, Mitochondrial Membrane Transport Proteins, Mice
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