Mitochondria‐specific overexpression of phospholipid hydroperoxide glutathione peroxidase (GPx4) attenuates ischemia/reperfusion (I/R) associated apoptosis

A primary determinant of the extent of I/R injury in the mitochondrion is antioxidant defense capacity. Phospholipid hydroperoxide glutathione peroxidase (PHGPx) is a unique antioxidant enzyme capable of reducing peroxidized acyl groups in phospholipids, providing protection to biological membranes. The goal of this study was to evaluate the impact of mitochondria‐specific overexpression of PHGPx on apoptotic susceptibility following cardiac I/R. Transgenic mice were created in which PHGPx was overexpressed in the mitochondrion (mPHGPx). MPHGPx and control hearts were subjected to global no‐flow ischemia (20 min) followed by reperfusion (90 min). MPHGPx subsarcolemmal mitochondria (SSM) displayeda decreased propensity for undergoing apoptosis as compared to I/R controls, with no differences in interfibrillar mitochondria (IFM). Caspase‐3 and −9 activities were decreased in mPHGPx SSM relative to I/R control ( P <0.05), with no differences in IFM. Mitochondrial permeability transition poreopening was decreased in mPHGPx SSM as compared to control( P <0.05), with no difference in IFM. Cyclophilin D was significantly decreased in mPHGPx SSM relative to I/R control ( P <0.05), with no differences in IFM. These results indicate that mitochondria‐specific PHGPx overexpression protects SSM against I/R‐associated apoptosis. ( Supported by NIH DP2 DK083095 , AHA 0815406D, AHA 0855484D, NIH T32 HL090610 )