Mitochondrial peptides: encoded in mitochondria, or aimed at them

Two meanings of one label

Peptides encoded by mitochondrial DNA

Review A 2020 review defines mitochondrial-derived peptides as small bioactive peptides encoded by short open reading frames in mitochondrial DNA.¹ It counts eight: MOTS-c in the 12S rRNA gene, and humanin with six small humanin-like peptides in the 16S rRNA gene.¹

Humanin

Cell study Humanin was identified in 2001 by a functional screen for genes that rescue neuronal cells from death caused by familial Alzheimer’s disease genes and by amyloid-beta.¹⁷ The short polypeptide was secreted into the culture medium, and its rescue activity depended on its exact sequence.¹⁷

Cell study In 2003 a second group reported that humanin, a peptide of 24 amino acids, binds the cell-death protein Bax and keeps it from moving to mitochondria.¹³ They noted that the mitochondrial genome contains an identical open reading frame, and speculated that humanin arose there.¹³ Later work describes it as encoded in the 16S rRNA region of mitochondrial DNA.¹⁸

Animal study In a 2020 paper, overexpressing humanin extended lifespan in the worm C. elegans, and middle-aged mice given a humanin analogue called HNG showed better metabolic measures and lower inflammatory markers.¹⁹

The small humanin-like peptides

Cell study A computer search of the same region, published in 2016, found six more peptides, now numbered SHLP1 to SHLP6.¹¹⁸ They differed in their effects on cell viability, and SHLP2 and SHLP3 reduced apoptosis and reactive oxygen species in culture.¹⁸

Animal study In clamp studies, SHLP2 increased glucose uptake and suppressed glucose production by the liver, and a later review lists it among the peptides tested in rodents.¹¹⁸

MOTS-c

Animal study MOTS-c, 16 amino acids long, was reported in 2015 from the 12S rRNA gene.¹² Its proposed route runs through the folate cycle to the kinase AMPK, and in mice MOTS-c treatment prevented diet-induced obesity and insulin resistance.¹²

Peptides designed to reach mitochondria

SS-31 is synthetic and comes from no genome.³ Its sequence is D-Arg-2,6-dimethyl-Tyr-Lys-Phe-NH2: four residues, with arginine in the mirror-image D form and a tyrosine that carries two added methyl groups.¹⁴ The article on peptide nomenclature and modifications explains this notation. PubChem lists the molecule as elamipretide, C32H49N9O5, 639.8 g/mol, with SS-31 and MTP-131 among its synonyms.²⁰ The letters SS stand for Szeto-Schiller, the class of tetrapeptides it leads.³

Cell study In 2004 a group that included Szeto and Schiller described cell-permeable peptides, built on alternating aromatic and basic residues, that concentrated about a thousandfold in the inner mitochondrial membrane.¹¹ They were framed as antioxidants: they reduced reactive oxygen species and cell death in cultured neuronal cells, and analogues without dimethyltyrosine did not inhibit mitochondrial swelling or the generation of reactive oxygen species.¹¹ That abstract names no individual peptide.¹¹

Cell study In 2013 SS-31 was shown to bind with high affinity to cardiolipin, an anionic phospholipid of the inner mitochondrial membrane that is required for the folds called cristae.² The peptide-lipid complex inhibited the peroxidase activity of cytochrome c.²

Animal study In the same paper, pretreating rats with SS-31 protected cristae membranes during renal ischemia and prevented mitochondrial swelling.²

Cell study A 2020 biophysical study added that SS-31 settles in the interfacial region of membranes in proportion to their surface charge, and alters their surface electrostatics without destabilizing the bilayer.³ The FDA label describes elamipretide as a mitochondrial cardiolipin binder.¹⁴

Human evidence

For the encoded peptides, the human data are measurements of the body’s own levels, and we found no trial result for any of them given to people.

Human study Circulating humanin was higher in the children of centenarians than in age-matched controls, and lower in people with Alzheimer’s disease and with the mitochondrial disorder MELAS.¹⁹ A ClinicalTrials.gov search on 8 October 2026 for humanin as an intervention returned three studies, none of which gives the peptide.⁴ One placebo-controlled trial of MOTS-c was registered and recruiting on that date, with no results posted.²¹

Elamipretide has been tested in randomized, placebo-controlled trials:

• Human study Barth syndrome. In a crossover trial in 12 people, neither primary endpoint was met in the randomized part; significant changes on both were reported at 36 weeks of an open-label extension with no placebo group.⁵
• Human study Primary mitochondrial myopathy. MMPOWER-3, a phase 3 trial in 218 people, did not meet its primary endpoints of walking distance and fatigue at 24 weeks.⁶
• Human study Heart failure. In PROGRESS-HF, 71 patients with reduced ejection fraction showed no significant difference from placebo in a cardiac volume measure after four weeks.⁷
• Human study Dry age-related macular degeneration. ReCLAIM-2, a phase 2 trial in 176 patients, did not meet its primary endpoints at 48 weeks, and reported nominal differences on a predefined retinal imaging measure.⁸

The label lists local site reactions as the most common adverse reactions, and says hypersensitivity reactions have been reported.¹⁴

The regulatory history of elamipretide

Each statement was checked against the authority’s own page on 8 October 2026.

• 10 October 2024. An FDA advisory committee met to discuss the new drug application for elamipretide in Barth syndrome, submitted by Stealth BioTherapeutics.²²
• 15 May 2025. The FDA issued a complete response letter, stating that it could not approve the application in its present form.⁹ It wrote that the only randomized, placebo-controlled study had not shown superiority to placebo on its primary endpoints, and that the open-label and externally controlled comparisons were open to bias.⁹ It added that knee extensor muscle strength could be a reasonable intermediate clinical endpoint for accelerated approval, and noted deficiencies at a manufacturing facility.⁹
• 19 September 2025. The FDA granted accelerated approval to Forzinity (elamipretide); the labelled indication is muscle strength in adults and children with Barth syndrome who weigh at least 30 kg.¹⁴¹⁶ The label says knee extensor strength rose during the extension period and not during the randomized trial, and the agency requires a randomized confirmatory trial.¹⁰¹⁴
• Review After approval. A 2026 summary calls elamipretide the first disease-specific treatment approved for Barth syndrome and says phase 3 development continues in dry age-related macular degeneration and mitochondrial myopathies.²³
• Canada. Health Canada’s Drug Product Database returned no product with elamipretide as an active ingredient.²⁴ A Health Canada advisory last updated on 9 April 2026 names SS-31 and MOTS-c among examples of unauthorized injectable peptide drugs it had seized.²⁵

The FDA approval covers one manufactured medicine, for one indication, in the United States. It does not extend to SS-31 supplied as a research material, which Horizon sells for laboratory research use only. How to weigh cell, animal and human findings is set out in the guide to evidence levels in peptide research.