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.