Ischemia causes AKI as a result of
ATP depletion, and rapid recovery of
ATP on reperfusion is important to minimize tissue damage.
ATP recovery is often delayed, however, because
ischemia destroys the mitochondrial cristae membranes required for mitochondrial
ATP synthesis. The mitochondria-targeted compound SS-31 accelerates
ATP recovery after
ischemia and reduces AKI, but its mechanism of action remains unclear. Here, we used a polarity-sensitive fluorescent analog of SS-31 to demonstrate that SS-31 binds with high affinity to
cardiolipin, an anionic
phospholipid expressed on the inner mitochondrial membrane that is required for cristae formation. In addition, the SS-31/
cardiolipin complex inhibited
cytochrome c peroxidase activity, which catalyzes
cardiolipin peroxidation and results in mitochondrial damage during
ischemia, by protecting its
heme iron. Pretreatment of rats with SS-31 protected cristae membranes during renal
ischemia and prevented mitochondrial swelling. Prompt recovery of
ATP on reperfusion led to rapid repair of
ATP-dependent processes, such as restoration of the actin cytoskeleton and cell polarity. Rapid recovery of
ATP also inhibited apoptosis, protected tubular barrier function, and mitigated renal dysfunction. In conclusion, SS-31, which is currently in clinical trials for
ischemia-reperfusion injury, protects mitochondrial cristae by interacting with
cardiolipin on the inner mitochondrial membrane.