SS-31 vs MOTS-c

Elamipretide (SS-31) is a mitochondria-targeting tetrapeptide that selectively binds cardiolipin in the inner mitochondrial membrane; in preclinical models this was associated with stabilized cristae, reduced oxidative stress and greater ATP production ¹. Biophysical work showed that SS-31 partitions into membrane interfaces and modulates surface electrostatics ². The FDA label describes it as a mitochondrial cardiolipin binder ³.

FDA granted accelerated approval on 19 September 2025 for Barth syndrome in patients weighing at least 30 kg, based on knee extensor muscle strength as an intermediate endpoint ^3,4. In the randomized crossover trial underlying the label, elamipretide was not superior to placebo on the 6-minute walk and fatigue primary endpoints ³. In the 218-participant MMPOWER-3 trial in primary mitochondrial myopathy, the difference in 6-minute walk distance versus placebo was -3.2 m (p = 0.69) ⁵.

MOTS-c is a 16-amino-acid peptide encoded by a short open reading frame in the mitochondrial 12S rRNA gene ⁶. In the founding study, it acted mainly on skeletal muscle, inhibited the folate cycle and de novo purine synthesis leading to AMPK activation, and in mice prevented age-dependent and high-fat-diet-induced insulin resistance and diet-induced obesity (animal data) ⁶. In mice of several ages, MOTS-c improved physical performance, and in humans exercise increased endogenous MOTS-c in skeletal muscle and circulation ⁷.

A 2023 review reported that plasma MOTS-c declines with age and that no effective method of applying it in the clinic had yet been developed ⁸. FDA states that it has not identified human exposure data for MOTS-c by any route ⁹.