TY - JOUR
T1 - Endoplasmic reticulum-mitochondria crosstalk in NIX-mediated murine cell death
AU - Diwan, Abhinav
AU - Matkovich, Scot J.
AU - Yuan, Qunying
AU - Zhao, Wen
AU - Yatani, Atsuko
AU - Brown, Joan Heller
AU - Molkentin, Jeffery D.
AU - Kranias, Evangelia G.
AU - Dorn, Gerald W.
PY - 2009/1/5
Y1 - 2009/1/5
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=61749087672&partnerID=8YFLogxK
U2 - 10.1172/JCI36445
DO - 10.1172/JCI36445
M3 - Article
C2 - 19065046
AN - SCOPUS:61749087672
SN - 0021-9738
VL - 119
SP - 203
EP - 212
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 1
ER -