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, John W. Elrod

Research output: Contribution to journalArticle

61 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)93-97
Number of pages5
JournalNature
Volume545
Issue number7652
DOIs
StatePublished - May 4 2017

Fingerprint

Homeostasis
Cell Death
Heart Failure
Gene Transfer Techniques
Tamoxifen
Sudden Death
Cardiac Myocytes
Superoxides
Cause of Death
Permeability
Necrosis
Ischemia
Pathology
Calcium
Therapeutics
mitochondrial permeability transition pore

Cite this

Luongo, T. S., Lambert, J. P., Gross, P., Nwokedi, M., Lombardi, A. A., Shanmughapriya, S., ... Elrod, J. W. (2017). The mitochondrial Na+/Ca2+ exchanger is essential for Ca2+ homeostasis and viability. Nature, 545(7652), 93-97. https://doi.org/10.1038/nature22082

The mitochondrial Na+/Ca2+ exchanger is essential for Ca2+ homeostasis and viability. / Luongo, Timothy S.; Lambert, Jonathan P.; Gross, Polina; Nwokedi, Mary; Lombardi, Alyssa A.; Shanmughapriya, Santhanam; Carpenter, April C.; Kolmetzky, Devin; Gao, Erhe; Van Berlo, Jop H.; Tsai, Emily J.; Molkentin, Jeffery D.; Chen, Xiongwen; Madesh, Muniswamy; Houser, Steven R.; Elrod, John W.

In: Nature, Vol. 545, No. 7652, 04.05.2017, p. 93-97.

Research output: Contribution to journalArticle

Luongo, TS, Lambert, JP, Gross, P, Nwokedi, M, Lombardi, AA, Shanmughapriya, S, Carpenter, AC, Kolmetzky, D, Gao, E, Van Berlo, JH, Tsai, EJ, Molkentin, JD, Chen, X, Madesh, M, Houser, SR & Elrod, JW 2017, 'The mitochondrial Na+/Ca2+ exchanger is essential for Ca2+ homeostasis and viability', Nature, vol. 545, no. 7652, pp. 93-97. https://doi.org/10.1038/nature22082
Luongo TS, Lambert JP, Gross P, Nwokedi M, Lombardi AA, Shanmughapriya S et al. The mitochondrial Na+/Ca2+ exchanger is essential for Ca2+ homeostasis and viability. Nature. 2017 May 4;545(7652):93-97. https://doi.org/10.1038/nature22082
Luongo, Timothy S. ; Lambert, Jonathan P. ; Gross, Polina ; Nwokedi, Mary ; Lombardi, Alyssa A. ; Shanmughapriya, Santhanam ; Carpenter, April C. ; Kolmetzky, Devin ; Gao, Erhe ; Van Berlo, Jop H. ; Tsai, Emily J. ; Molkentin, Jeffery D. ; Chen, Xiongwen ; Madesh, Muniswamy ; Houser, Steven R. ; Elrod, John W. / The mitochondrial Na+/Ca2+ exchanger is essential for Ca2+ homeostasis and viability. In: Nature. 2017 ; Vol. 545, No. 7652. pp. 93-97.
@article{62fce511f5b046af980f955e685df703,
title = "The mitochondrial Na+/Ca2+ exchanger is essential for Ca2+ homeostasis and viability",
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.",
author = "Luongo, {Timothy S.} and Lambert, {Jonathan P.} and Polina Gross and Mary Nwokedi and Lombardi, {Alyssa A.} and Santhanam Shanmughapriya and Carpenter, {April C.} and Devin Kolmetzky and Erhe Gao and {Van Berlo}, {Jop H.} and Tsai, {Emily J.} and Molkentin, {Jeffery D.} and Xiongwen Chen and Muniswamy Madesh and Houser, {Steven R.} and Elrod, {John W.}",
year = "2017",
month = "5",
day = "4",
doi = "10.1038/nature22082",
language = "English (US)",
volume = "545",
pages = "93--97",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7652",

}

TY - JOUR

T1 - The mitochondrial Na+/Ca2+ exchanger is essential for Ca2+ homeostasis and viability

AU - Luongo, Timothy S.

AU - Lambert, Jonathan P.

AU - Gross, Polina

AU - Nwokedi, Mary

AU - Lombardi, Alyssa A.

AU - Shanmughapriya, Santhanam

AU - Carpenter, April C.

AU - Kolmetzky, Devin

AU - Gao, Erhe

AU - Van Berlo, Jop H.

AU - Tsai, Emily J.

AU - Molkentin, Jeffery D.

AU - Chen, Xiongwen

AU - Madesh, Muniswamy

AU - Houser, Steven R.

AU - Elrod, John W.

PY - 2017/5/4

Y1 - 2017/5/4

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85018437204&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85018437204&partnerID=8YFLogxK

U2 - 10.1038/nature22082

DO - 10.1038/nature22082

M3 - Article

VL - 545

SP - 93

EP - 97

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7652

ER -