The Mitochondrial Na/Ca Exchanger is Essential for Ca Homeostasis and Viability

Overview

Journal Nature

Specialty Science

Date 2017 Apr 27

PMID 28445457

Citations 198

Authors

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

Affiliations

Soon will be listed here.

Abstract

Mitochondrial calcium (Ca) 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 exchanger (NCLX), which is proposed to be the primary mechanism for Ca 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 Ca 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 Ca clearance, preventing permeability transition and protecting against ischaemia-induced cardiomyocyte necrosis and heart failure. These results demonstrate the essential nature of Ca efflux in cellular function and suggest that augmenting Ca efflux may be a viable therapeutic strategy in disease.

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