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 Ca2+ homeostasis is essential for cell survival, and that the anti-apoptotic protein Bcl-2 is able to maintain a threshold level of mitochondrial Ca2+ by the inhibition of permeability transition. To test whether Bcl-2 also affects the mitochondrial Na+-Ca2+ exchange (NCE), a major efflux pathway for mitochondrial Ca2+, studies using transgenic mice that overexpress Bcl-2 in the heart have been performed. NCE activity was determined as the Na+-dependent Ca2+ 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 Ca2+ level, enhanced formation of NADH and enhanced oxidation of pyruvate, an NAD(+)-linked substrate, Furthermore, there was induction of cellular Ca2+ transport proteins including the Na+-Ca2+ exchanger of the sarcolemma (NCX). Bcl-2 not only stimulates NCX expression in the sarcolemma. but also attenuates' the Na+-Ca2+ exchange in the mitochondria, These results are consistent with the protection by Bcl-2 against apoptosis in heart following ischemia/reperfusion. (C) 2001 Academic Press.