Mitochondrial Peptides
Explained

What are mitochondrial peptides?

"Mitochondrial peptides" covers two different groups. Mitochondria-derived peptides, or MDPs (also written mitochondrial-derived peptides), are short peptides encoded by small open reading frames in mitochondrial DNA, beyond its 13 classic protein-coding genes. Examples are humanin, MOTS-c and the small humanin-like peptides SHLP1 to SHLP6 (Lee et al., 2013; Cobb et al., 2016).

Mitochondria-targeted peptides are synthetic peptides designed to enter cells and collect at mitochondria. The best known, SS-31 (elamipretide), concentrates in the inner mitochondrial membrane and binds cardiolipin there (Zhao et al., 2004; Birk et al., 2013). Disguised Alpha supplies MOTS-c, humanin and SS-31 as lyophilized powders for laboratory research use only. Nothing on this page is guidance for use in people.

Mitochondria-derived peptides (MDPs)

Human mitochondrial DNA is a circle of 16,569 base pairs with 37 genes: 13 for proteins, 22 for transfer RNAs and 2 for ribosomal RNAs. MDPs come from short reading frames inside the two ribosomal RNA genes: humanin and the SHLPs in the 16S rRNA gene, MT-RNR2, and MOTS-c in the 12S rRNA gene, MT-RNR1 (Cobb et al., 2016; Lee et al., 2015). A 2013 review called humanin the first of a putative set of MDPs, with many more possible reading frames scattered through the mitochondrial genome (Lee et al., 2013).

Discovery history: 2001, 2015, 2016

• 2001, humanin. A functional expression screen found a gene for a short secreted polypeptide that abolished neuronal cell death caused by familial Alzheimer's disease genes and amyloid-beta (Hashimoto et al., 2001). Its clones matched part of the mitochondrial 16S rRNA, with a 75-base-pair reading frame for a 24-residue peptide. Two other groups cloned humanin independently, as a binding partner of IGFBP-3 and of Bax (Lee et al., 2013).
• 2015, MOTS-c. Searching mitochondrial DNA for more frames like humanin's, Lee and colleagues found a 51-base-pair frame in the 12S rRNA gene encoding a 16-residue peptide, the mitochondrial open reading frame of the 12S rRNA type-c (Lee et al., 2015).
• 2016, the SHLPs. An in silico search of the 16S rRNA region found six more frames for peptides of 20 to 38 residues, named small humanin-like peptides 1 to 6 (Cobb et al., 2016).

Mitochondria-targeted peptides: SS-31

SS-31 is a synthetic Szeto-Schiller tetrapeptide, D-Arg-Dmt-Lys-Phe-NH2, where Dmt is 2,6-dimethyltyrosine (PubChem CID 11764719). Its international nonproprietary name is elamipretide, and no genome encodes it. In the 2004 founding study, peptides of this alternating aromatic and basic design were cell-permeable and concentrated about 1000-fold in the inner mitochondrial membrane (Zhao et al., 2004). A fluorescent analog later showed SS-31 binding cardiolipin, the anionic inner-membrane phospholipid that cristae need to form (Birk et al., 2013). For SS-31, "mitochondrial" describes where it goes, not where it comes from.

Mitochondrial peptides at a glance

Sources: Lee et al., 2013 and Bodzioch et al., 2009 (humanin), Lee et al., 2015 (MOTS-c), Cobb et al., 2016 (SHLPs), Birk et al., 2013 and PubChem CID 11764719 (SS-31).

What each has been studied for

Humanin

Work with purified proteins, cell lines and isolated mitochondria found humanin binding the apoptosis proteins Bax, Bid and BimEL. In rats, humanin and its analogs, infused into the brain or the bloodstream, raised whole-body insulin sensitivity during insulin clamps, in part through hypothalamic STAT3. Several animal studies used HNG, a different molecule with glycine at position 14, reported as about 1000-fold more potent (Lee et al., 2013).

MOTS-c

In cell culture and mice, MOTS-c inhibited the folate cycle and the de novo purine synthesis tethered to it, leading to AMPK activation, with skeletal muscle as the apparent main target. In mice it prevented high-fat-diet-induced insulin resistance and diet-induced obesity (Lee et al., 2015).

SHLPs

In mouse NIT-1 beta cells and human 22Rv1 prostate cancer cells, SHLP2 and SHLP3 raised cell viability and lowered apoptosis and reactive oxygen species, while SHLP6 increased apoptosis. In 22Rv1 cells, SHLP2 and SHLP3 raised oxygen consumption and cellular ATP. In rats, SHLP2 infused into the brain raised the glucose infusion rate during an insulin clamp by about 50 percent; SHLP3 did not (Cobb et al., 2016).

SS-31

In N2A neuronal cells and isolated mitochondria, the founding peptides lowered reactive oxygen species and cell death and inhibited the permeability transition and swelling (Zhao et al., 2004). Bound to cardiolipin, SS-31 inhibited cytochrome c peroxidase activity, and in rats given SS-31 before renal ischemia, cristae membranes were preserved (Birk et al., 2013).

Human research status

SS-31 (elamipretide). In placebo-controlled trials, a phase 3 trial in 218 participants with primary mitochondrial myopathy met neither primary endpoint (Karaa et al., 2023). A phase 2 trial in 71 patients with heart failure with reduced ejection fraction found no significant change in left ventricular end systolic volume at four weeks (Butler et al., 2020). In Barth syndrome, a 12-subject crossover trial met neither primary endpoint, and its open-label extension reported gains at 36 weeks (Reid Thompson et al., 2021).

In September 2025, elamipretide received accelerated approval in the United States as Forzinity, with an indication concerning muscle strength in adult and pediatric patients with Barth syndrome who weigh at least 30 kilograms. It was the first approval specific to that condition, and a confirmatory trial is required (Shirley, 2026; FDA announcement). The SS-31 sold here is research-grade powder, not that drug product, and not for use in people.

MOTS-c and humanin. We found no published trial in PubMed that gave either peptide to people; human studies measure them. MOTS-c has been detected in human plasma by ELISA (Lee et al., 2015). In a randomized study of 30 participants, plasma humanin rose after 45 minutes of cycling, while MOTS-c showed only a trend (von Walden et al., 2021). Neither is an approved drug. The 2026 WADA Prohibited List names MOTS-c in class S4.4.1, metabolic modulators, prohibited at all times.

Open questions

Mitochondrial or cytoplasmic translation?

Mitochondria read some codons differently from the rest of the cell, so one stretch of DNA can give different peptides depending on where it is translated. For humanin, versions made with either code were active, leaving the site undetermined (Lee et al., 2013).

For MOTS-c, the mitochondrial code turns the frame into tandem start and stop codons, so its discoverers concluded it is made in the cytoplasm from a transcript exported out of mitochondria (Lee et al., 2015). In rat cells, rat humanin production fell when mitochondrial DNA was depleted and was unaffected by cycloheximide, a blocker of cytoplasmic translation, pointing to translation inside mitochondria (Paharkova et al., 2015).

Mitochondrial or nuclear genes? The NUMT problem

NUMTs, copies of mitochondrial DNA inserted into the nuclear genome, are generally considered pseudogenes, and a 2013 review judged the case for humanin's mitochondrial origin strong but circumstantial, with a NUMT source not ruled out (Lee et al., 2013). The human nuclear genome carries 13 MT-RNR2-like loci predicted to keep full humanin-like reading frames, at least ten of them expressed in human tissues (Bodzioch et al., 2009).

So a humanin signal in human cells does not by itself show which genome made it. Rats appear to lack nuclear copies of humanin and MOTS-c, so rat cells are used to test mitochondrial origin (Paharkova et al., 2015; Lee et al., 2015). For SHLP2 and SHLP3, PCR detected both mitochondrial and nuclear versions (Cobb et al., 2016).

What do the assays measure?

Method matters. A mass spectrometry method validated to anti-doping standards could not confirm the 45.9 to 218.5 nanograms per milliliter of MOTS-c that a commercial ELISA reported in 20 healthy subjects (Knoop et al., 2019), so values from different assays may not be comparable.

Key sources

1. Lee C, Yen K, Cohen P. "Humanin: a harbinger of mitochondrial-derived peptides?" Trends Endocrinol Metab. 2013. PMID 23402768. DOI 10.1016/j.tem.2013.01.005. Review, including NUMTs.
2. Lee C, et al. "The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance." Cell Metab. 2015. PMID 25738459. DOI 10.1016/j.cmet.2015.02.009. MOTS-c's discovery.
3. Cobb LJ, et al. "Naturally occurring mitochondrial-derived peptides are age-dependent regulators of apoptosis, insulin sensitivity, and inflammatory markers." Aging (Albany NY). 2016. PMID 27070352. DOI 10.18632/aging.100943. The SHLPs.
4. Zhao K, et al. "Cell-permeable peptide antioxidants targeted to inner mitochondrial membrane inhibit mitochondrial swelling, oxidative cell death, and reperfusion injury." J Biol Chem. 2004. PMID 15178689. DOI 10.1074/jbc.M402999200. The SS peptides.
5. Shirley M. "Elamipretide: First Approval." Drugs. 2026. PMID 41335372. DOI 10.1007/s40265-025-02269-8. Regulatory history.

Frequently asked questions

What are MDPs?

Mitochondrial derived peptides, also written mitochondria-derived peptides: short peptides from small reading frames in mitochondrial DNA, in addition to its 13 classic protein-coding genes (Lee et al., 2013). In immunology, MDP can also mean muramyl dipeptide, an unrelated bacterial cell wall fragment.

Is SS-31 a mitochondrial-derived peptide?

No. SS-31 is a mitochondria-targeted peptide: a synthetic tetrapeptide that no genome encodes, grouped with mitochondrial peptides because it concentrates in the inner mitochondrial membrane (Zhao et al., 2004).

How many mitochondria-derived peptides are known?

The first eight described were humanin, MOTS-c and SHLP1 to SHLP6, all from the two mitochondrial ribosomal RNA genes (Lee et al., 2015; Cobb et al., 2016). Many more possible reading frames exist in mitochondrial DNA (Lee et al., 2013).

Have mitochondrial peptides been tested in people?

Elamipretide, the drug form of SS-31, has been through placebo-controlled trials and received US accelerated approval in September 2025 (Shirley, 2026). Published human studies of MOTS-c and humanin measure the peptides in blood (von Walden et al., 2021).

What is the difference between MOTS-c and humanin?

Humanin (24 residues, 16S rRNA gene) binds apoptosis proteins and IGFBP-3 and signals through cell-surface receptors (Lee et al., 2013). MOTS-c (16 residues, 12S rRNA gene) is reported to act through the folate cycle and AMPK, mainly in skeletal muscle (Lee et al., 2015).

Where can researchers buy mitochondrial peptides?

Disguised Alpha sells MOTS-c (10MG and 40MG), Humanin (10MG) and SS-31 (10MG and 50MG) as lyophilized powders for laboratory research, with certificates on each product page and in the COA portal.

Related guides

• MOTS-c research guide
• Humanin research guide
• SS-31 research guide
• MOTS-c vs 5-Amino-1MQ: research comparison
• 5-Amino-1MQ research guide
• NAD+ research guide
• Mitochonic Acid 5 (MA-5) research guide
• COA portal: published certificates, by lot
• Research hub

Disguised Alpha products are for research use only. They have not been evaluated for safety or effectiveness in humans. Not for human consumption. All products are intended for laboratory research purposes only.