Mitochondrial-derived peptides are short peptides encoded not by the nuclear genome but by small open reading frames inside mitochondrial DNA itself. The family is small and comparatively young: humanin was described in 2001, MOTS-c in 2015, and the six small humanin-like peptides (SHLPs) in 2016. This article sets out what the peer-reviewed literature reports about each of them, where that evidence stops, and why one compound routinely filed alongside them — SS-31 — does not belong to the family at all.
Everything below describes published experimental work in cell culture, in rodents, or as observational measurements in people. It is not a description of the properties, effects or suitability of anything Peptivitalis supplies. All material sold by Peptivitalis is supplied for laboratory research use only and is not for human consumption.
What “mitochondrial-derived” actually means
Human mitochondrial DNA is a small circular genome, and for decades it was described as encoding thirteen proteins, all of them components of the respiratory chain. Mitochondrial-derived peptides are a later addition to that list. They are translated from short open reading frames sitting within the mitochondrial ribosomal RNA genes — regions previously assumed to be structural rather than protein-coding.
The two best-characterised examples illustrate the pattern. MOTS-c is encoded by a short open reading frame of the mitochondrial 12S rRNA gene and is sixteen amino acids long [6]. Humanin is encoded within the 16S rRNA gene and is translated as either a 21- or a 24-residue peptide depending on where translation occurs [6]. The SHLPs come from the same 16S region as humanin [3][5].
That shared origin is the whole basis of the category. A peptide is a mitochondrial-derived peptide because of where its sequence comes from, not because of what it does or where it acts. This matters for anyone sorting a catalogue, because several unrelated synthetic compounds are marketed with similar language.
Humanin: the first mitochondrial-derived peptide
Humanin was identified in 2001 by Hashimoto and colleagues, working from surviving neurons in occipital lobe tissue of an Alzheimer’s disease patient. They reported a factor that abolished neuronal cell death caused by a range of familial Alzheimer’s disease genes and by amyloid-beta, and named it humanin [1]. The work was done in cultured neuronal cells; the paper is a cell-death rescue study, not a treatment study.
A 2022 review in the Journal of Clinical Investigation summarises what has accumulated since: humanin has been reported to act through receptor complexes involving gp130 and WSX1, with downstream AKT, ERK1/2 and STAT3 signalling; circulating humanin declines with age in humans; and in model organisms, overexpression extended lifespan in a manner dependent on FOXO signalling [5].
MOTS-c: the most studied member of the family
MOTS-c — mitochondrial open reading frame of the 12S rRNA type-c — was described by Lee and colleagues in Cell Metabolism in 2015 [2]. The proposed mechanism is indirect and unusual: MOTS-c interferes with the folate cycle, AICAR accumulates as a consequence, and AICAR activates AMP-activated protein kinase [2][6]. The 2023 Journal of Translational Medicine review describes this folate–AICAR–AMPK route as the principal pathway reported for the peptide [6].
In the original work, the experimental system was mice on a high-fat diet and cultured cells; the reported outcomes were on weight gain and insulin sensitivity in those mice [2][5]. Later work added a second mechanism: under metabolic stress, MOTS-c translocates to the nucleus and associates with transcription factors including NRF1, so the peptide is described as acting on nuclear gene expression rather than only within the mitochondrion [5].
Human observational data exist and are worth separating from the interventional work. Circulating MOTS-c has been reported to decrease with age, and a naturally occurring variant of the peptide, K14Q, is reported as bioinactive and associated with type 2 diabetes susceptibility in Japanese men [5]. These are associations measured in people, not outcomes of administering anything to people.
MOTS-c and exercise
The most-cited recent MOTS-c paper is Reynolds and colleagues in Nature Communications in 2021 [4]. It has two halves. In young male volunteers, a single bout of exercise was followed by an approximately twelve-fold rise in MOTS-c in skeletal muscle and a smaller rise in circulating levels — an observation about endogenous peptide, with nothing administered. In the second half, MOTS-c was administered to mice at three ages, and the authors reported improvements in treadmill running capacity and, in the oldest animals, in grip strength, stride length and walking capacity, with a trend towards increased median and maximum lifespan [4].
The framing that followed — MOTS-c as an “exercise mimetic” [5] — is a shorthand for that rodent result plus the human correlation. It is not a finding in humans, and the mouse work is the only interventional half of the paper.
The SHLPs: six more short open reading frames
In 2016 Cobb and colleagues searched the mitochondrial genome region around humanin computationally and reported six further peptides, which they named small humanin-like peptides 1 to 6 [3]. In cultured cells, SHLP2 and SHLP3 were reported to reduce apoptosis, suppress reactive oxygen species generation and improve mitochondrial function; the same paper reported effects on adipocyte differentiation and on glucose metabolism, assessed by hyperinsulinaemic–euglycaemic clamp [3]. Circulating SHLP2 declined with age, mirroring humanin.
The SHLPs are not uniform. SHLP6 has been reported to induce apoptosis rather than prevent it [5], which is a useful corrective to any account that treats the whole family as a single protective class.
Mitochondria-derived is not the same as mitochondria-targeted
SS-31 is regularly listed next to MOTS-c under headings such as “mitochondrial peptides”. It is a different kind of molecule. SS-31 is a synthetic tetrapeptide, designed rather than discovered, and it is not encoded anywhere in mitochondrial DNA. Zhao and colleagues characterised the Szeto–Schiller series in 2004 as cell-permeable peptide antioxidants that concentrate at the inner mitochondrial membrane [7]. It is targeted to the mitochondrion; it is not derived from it.
SS-31 also has a regulatory status the mitochondrial-derived peptides do not. As elamipretide, it received FDA accelerated approval on 19 September 2025 under the brand name FORZINITY (Stealth BioTherapeutics, application 215244) to improve muscle strength in patients with Barth syndrome. It is an approved prescription medicine in the United States. Full details are on the SS-31 monograph.
NAD+ is a third thing again — a coenzyme central to mitochondrial redox chemistry, not a peptide at all. It is characterised in the NAD+ index entry rather than treated as a member of this family.
What the evidence does not cover
The interventional literature on mitochondrial-derived peptides is almost entirely preclinical. For MOTS-c, the administration studies are in mice and in cultured cells; the human data are measurements of endogenous peptide and genetic-variant associations. For humanin and the SHLPs, the position is the same or thinner. No mitochondrial-derived peptide holds a marketing authorisation anywhere, and none has an established human safety profile in the regulatory sense.
The 2022 JCI review also raises a methodological caveat worth carrying forward: detection of short open reading frames by ribosome profiling can call very large numbers of candidate sequences across experiments, which creates reproducibility problems, and mitochondrial DNA editing lacks the fidelity that would make genomic findings straightforward to validate [5]. The family is real; the boundary of the family is still being drawn.
Specification and availability
Of the mitochondrial-derived peptides discussed here, MOTS-c is the one Peptivitalis stocks. MOTS-c 10 mg is supplied as a lyophilised powder, ≥98% purity by RP-HPLC, with a certificate of analysis for the lot supplied. The full entry, including identity data and the citation list, is at the MOTS-c monograph; the other nineteen compounds we stock are indexed in the Compound Index.
Research use only. Not for human consumption. Nothing on this page is dosing, protocol, handling or administration guidance, and nothing here is a therapeutic or health claim. Material supplied by Peptivitalis is intended for in-vitro laboratory research by qualified personnel.
Literature
- [1] Hashimoto Y, Niikura T, Tajima H, et al. A rescue factor abolishing neuronal cell death by a wide spectrum of familial Alzheimer’s disease genes and Abeta. Proc Natl Acad Sci U S A. 2001;98(11):6336–6341. PMID 11371646.
- [2] Lee C, Zeng J, Drew BG, et al. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metab. 2015;21(3):443–454. PMCID PMC4350682.
- [3] Cobb LJ, Lee C, Xiao J, et al. Naturally occurring mitochondrial-derived peptides are age-dependent regulators of apoptosis, insulin sensitivity, and inflammatory markers. Aging (Albany NY). 2016;8(4):796–809. DOI 10.18632/aging.100943. PMID 27070352.
- [4] Reynolds JC, Lai RW, Woodhead JST, et al. MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis. Nat Commun. 2021;12:470. DOI 10.1038/s41467-020-20790-0.
- [5] Miller B, Kim SJ, Kumagai H, Yen K, Cohen P. Mitochondria-derived peptides in aging and healthspan. J Clin Invest. 2022;132(9):e158449. DOI 10.1172/JCI158449.
- [6] Wan W, Zhang L, Lin Y, et al. Mitochondria-derived peptide MOTS-c: effects and mechanisms related to stress, metabolism and aging. J Transl Med. 2023;21:36. DOI 10.1186/s12967-023-03885-2.
- [7] Zhao K, Zhao GM, Wu D, et al. Cell-permeable peptide antioxidants targeted to inner mitochondrial membrane inhibit mitochondrial swelling, oxidative cell death, and reperfusion injury. J Biol Chem. 2004;279(33):34682–34690. PMID 15178689. DOI 10.1074/jbc.M402999200.