SELECTIVE TARGETING OF CYTOCHROME C–CARDIOLIPIN COMPLEX TO PROTECT MITOCHONDRIAL CRISTAE AND INHIBIT APOPTOSIS

Abstract

Cardiolipin (CL) plays a major role in mitochondrial cristae formation and ATP synthesis. Peroxidation of CL during mitochondrial oxidative stress causes cristae remodeling and initiates apoptosis. Cardiolipin peroxidation may occur by free radical lipid oxidation or by peroxidase activity of cyt c. Cyt c peroxidase activity is greatly enhanced when it is in a complex with CL, whereby an acyl chain impales cyt c, exposing the heme Fe to H2O2. Here we report the first mitochondria‐targeted compound that selectively targets CL and inhibits cyt c peroxidase activity. Using a polarity‐sensitive amino acid (aladan), we demonstrate that SS‐31, a tetrapeptide that targets inner mitochondrial membrane, interacts with CL via electrostatic and hydrophobic interactions. SS‐31 inhibits cyt c peroxidase activity induced by CL in a dose‐dependent manner. Circular dichroism indicates that this inhibitory activity is due to the ability of the [CL/SS‐31] complex to protect the heme Fe. This inhibition does not rely on the ability of SS‐31 to scavenge H2O2 as the non‐scavenging analog (SS‐20) also inhibits cyt c peroxidase. Both SS‐31 and SS‐20 inhibits basal and Ca2+‐stimulated cyt c peroxidase activity. Furthermore, we have evidence that SS‐31 and SS‐20 prevent cristae remodeling during ischemia‐reperfusion (IR) and inhibit apoptosis. SS‐31 is the first cyt c peroxidase inhibitor in clinical trial for cardiorenal IR injury