Cardiolipin

Cardiolipin (CL) is a dimeric phospholipid found almost exclusively in the inner mitochondrial membrane (IMM), constituting roughly 15–20 % of total lipid content. Its four acyl chains — predominantly linoleic acid in healthy heart and skeletal muscle, forming tetra-linoleoyl cardiolipin (TLCL) — generate the negative membrane curvature needed for cristae architecture and stabilize respiratory supercomplexes (complexes I, III, and IV) as molecular glue at their interfaces (Corey et al., 2022). ROS-driven oxidation introduces hydroperoxide groups that disrupt curvature, destabilize supercomplexes, and convert cytochrome c into a cardiolipin peroxidase; oxidized CL loses IMM affinity, releasing cytochrome c into the cytosol to activate caspases and trigger apoptosis (Kagan et al., 2005). With aging, total CL and the TLCL fraction decline in cardiac, hepatic, brain, and skeletal muscle mitochondria in animal models while oxidized species rise; in aged rat hearts, ischemia produces approximately three- to four-fold greater accumulation of an oxidized CL species than in adult hearts without a change in total CL (Lesnefsky and Hoppel, 2008). Evidence remains largely experimental — rodent, fish, and primate models — with human data sparse and mostly associational (Yoo et al., 2025). One approved therapy targets CL: elamipretide (SS-31, Forzinity), a mitochondria-targeted tetrapeptide that received FDA accelerated approval for Barth syndrome — a genetic CL-remodeling disorder — in September 2025; trials in heart failure and mitochondrial myopathy are ongoing.