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

Producción científica: Articlerevisión exhaustiva

296 Citas (Scopus)

Resumen

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.

Idioma originalEnglish (US)
Páginas (desde-hasta)93-97
Número de páginas5
PublicaciónNature
Volumen545
N.º7652
DOI
EstadoPublished - may 4 2017
Publicado de forma externa

ASJC Scopus subject areas

  • General

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