SS-31 stabilizes cardiolipin and lowers peroxidation

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SS-31 (elamipretide) stabilizes cardiolipin and lowers mitochondrial lipid peroxidation via several linked mechanisms
SS-31 is a small, cationic tetrapeptide that accumulates at the inner mitochondrial membrane and binds with high affinity to anionic cardiolipin via electrostatic and hydrophobic interactions. This interaction helps maintain cardiolipin’s physical state and supports cristae structure, preserving electron transport chain organization and mitochondrial membrane potential

In cell and animal models, SS-31 decreases mitochondrial lipid peroxidation markers (e.g., MDA) and attenuates ferroptosis and oxidative injury, consistent with a mitochondria-targeted antioxidant effect centered on cardiolipin protection.
The dimethyl-tyrosine residue in SS-31 can form relatively unreactive tyrosyl radicals that dimerize, enabling some direct scavenging of oxygen radicals and inhibition of polyunsaturated lipid (e.g., linoleic acid, LDL) oxidation.

SS-31 binding to cardiolipin provides key mitochondrial benefits by preserving inner membrane structure and function during stress like ischemia-reperfusion
It enhances oxidative phosphorylation efficiency, boosts complex IV activity in supercomplexes, and supports ATP-dependent processes like cytoskeletal repair.
It interacts electrostatically and hydrophobically with cardiolipin, maintaining cristae architecture essential for electron transport chain (ETC) supercomplex assembly.
This prevents mitochondrial swelling and fragmentation, ensuring efficient electron flow and membrane potential stability.

These effects limit apoptosis, preserve barrier function (e.g., in kidney tubules), and mitigate oxidative stress/ferroptosis across models like heart failure and Barth syndrome.