Regulation of sodium-calcium exchange and mitochondrial energetics by Bcl-2 in the heart of transgenic mice.
Our previous work in cultured cells has shown that the maintenance of mitochondrial Ca(2+) homeostasis is essential for cell survival, and that the anti-apoptotic protein Bcl-2 is able to maintain a threshold level of mitochondrial Ca(2+) by the inhibition of permeability transition. To test whether Bcl-2 also affects the mitochondrial Na(+)-Ca(2+) exchange (NCE), a major efflux pathway for mitochondrial Ca(2+), studies using transgenic mice that overexpress Bcl-2 in the heart have been performed. NCE activity was determined as the Na(+)-dependent Ca(2+) efflux in the isolated mitochondria. Overexpression of Bcl-2 led to a significant reduction of NCE activity as well as increased resistance to permeability transition in the mitochondria of transgenic heart. This was accompanied by increased matrix Ca(2+) level, enhanced formation of NADH and enhanced oxidation of pyruvate, an NAD(+)-linked substrate. Furthermore, there was induction of cellular Ca(2+) transport proteins including the Na(+)-Ca(2+) exchanger of the sarcolemma (NCX). Bcl-2 not only stimulates NCX expression in the sarcolemma but also attenuates the Na(+)-Ca(2+) exchange in the mitochondria. These results are consistent with the protection by Bcl-2 against apoptosis in heart following ischemia/reperfusion.
Zhu
L
L
Department of Pathology, Wayne State University School of Medicine, Detroit, Michigan 48201, USA.
Yu
Y
Y
Chua
B H
BH
Ho
Y S
YS
Kuo
T H
TH
D000818:Animals; D002118:Calcium / Q000378:metabolism; D005786:Gene Expression Regulation; D006706:Homeostasis; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008929:Mitochondria, Heart / Q000378:metabolism*; D009243:NAD / Q000378:metabolism; D010539:Permeability; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics* / Q000378:metabolism*; D012508:Sarcolemma / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000378:metabolism*
D019253:Proto-Oncogene Proteins c-bcl-2; D019831:Sodium-Calcium Exchanger; D009243:NAD; D002118:Calcium