Transgenic Expression of Bcl-2 Modulates Energy Metabolism, Prevents Cytosolic Acidification During Ischemia, and Reduces Ischemia/Reperfusion Injury

Abstract

The antiapoptotic protein Bcl-2 is targeted to the mitochondria, but it is uncertain whether Bcl-2 affects only myocyte survival after ischemia, or whether it also affects metabolic functions of mitochondria during ischemia. Hearts from mice overexpressing human Bcl-2 and from their wild-type littermates (WT) were subjected to 24 minutes of global ischemia followed by reperfusion. During ischemia, the decrease in pH i and the initial rate of decline in ATP were significantly reduced in Bcl-2 hearts compared with WT hearts ( P <0.05). The reduced acidification during ischemia was dependent on the activity of mitochondrial F 1 F 0 -ATPase. In the presence of oligomycin (Oligo), an F 1 F 0 -ATPase inhibitor, the decrease in pH i was attenuated in WT hearts, but in Bcl-2 hearts, Oligo had no additional effect on pH i during ischemia. Likewise, addition of Oligo to WT hearts slowed the rate of decline in ATP during ischemia to a level similar to that observed in Bcl-2 hearts, but addition of Oligo had no significant effect on the rate of decline in ATP in Bcl-2 hearts during ischemia. These data are consistent with Bcl-2–mediated inhibition of consumption of glycolytic ATP. Furthermore, mitochondria from Bcl-2 hearts have a reduced rate of consumption of ATP on uncoupler addition. This could be accomplished by limiting ATP entry into the mitochondria through the voltage-dependent anion channel, and/or the adenine nucleotide transporter, or by direct inhibition of the F 1 F 0 -ATPase. Immunoprecipitation showed greater interaction between Bcl-2 and voltage-dependent anion channel during ischemia. These data indicate that Bcl-2 modulation of metabolism contributes to cardioprotection.