Endoplasmic reticulum–mitochondria crosstalk in NIX-mediated murine cell death
Abhinav Diwan, … , Evangelia G. Kranias, Gerald W. Dorn II
Abhinav Diwan, … , Evangelia G. Kranias, Gerald W. Dorn II
Published December 8, 2008
Citation Information: J Clin Invest. 2009;119(1):203-212. https://doi.org/10.1172/JCI36445.
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Research Article Cardiology

Endoplasmic reticulum–mitochondria crosstalk in NIX-mediated murine cell death

Abstract

Transcriptional upregulation of the proapoptotic BCL2 family protein NIX limits red blood cell formation and can cause heart failure by inducing cell death, but the requisite molecular events are poorly defined. Here, we show complementary mechanisms for NIX-mediated cell death involving direct and ER/sarcoplasmic reticulum–mediated (ER/SR-mediated) mitochondria disruption. Endogenous cardiac NIX and recombinant NIX localize both to the mitochondria and to the ER/SR. In genetic mouse models, cardiomyocyte ER/SR calcium stores are proportional to the level of expressed NIX. Whereas Nix ablation was protective in a mouse model of apoptotic cardiomyopathy, genetic correction of the decreased SR calcium content of Nix-null mice restored sensitivity to cell death and reestablished cardiomyopathy. Nix mutants specific to ER/SR or mitochondria activated caspases and were equally lethal, but only ER/SR-Nix caused loss of the mitochondrial membrane potential. These results establish a new function for NIX as an integrator of transcriptional and calcium-mediated signals for programmed cell death.

Authors

Abhinav Diwan, Scot J. Matkovich, Qunying Yuan, Wen Zhao, Atsuko Yatani, Joan Heller Brown, Jeffery D. Molkentin, Evangelia G. Kranias, Gerald W. Dorn II

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Figure 6

Mechanisms of Nix-induced cell death.

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Mechanisms of Nix-induced cell death. Transcriptionally induced NIX is t...
Transcriptionally induced NIX is targeted to the mitochondria and ER/SR and activates programmed cell death in cells via a canonical mitochondrial pathway and what we believe is a novel ER/SR pathway. Mitochondria-targeted Nix causes mitochondrial outer membrane permeabilization, likely in coordination with Bax and Bak, leading to cytochrome c release, apoptosome formation, caspase 3 activation and apoptotic cell death. ER/SR-targeted Nix contributes to ER/SR calcium overload. This sensitizes cells to environmental stimuli, resulting in local calcium release at junctional “hot spots” with mitochondria. Released calcium is taken up by a mitochondrial uniporter, causing intramitochondrial calcium overload that triggers mitochondrial permeability pore formation with loss of mitochondrial potential, mitochondrial swelling, and release of essential mitochondrial proteins, preventing ATP generation with resultant bioenergetic failure. This is rapidly followed by failure of energy-dependent, plasma membrane–localized ion transporters, causing intracellular ion overload, cellular swelling and rupture, and necrotic cell death. MPTP, mitochondrial permeability transition pore.