Mitochondrial peptides: humanin, MOTS-c and SS-31 explained

What the two meanings of mitochondrial peptides are

Mitochondria are small parts of cells that help make energy. They carry their own small set of DNA, called mitochondrial DNA. A 2024 review says human mitochondrial DNA has 16,569 DNA letters and 37 genes.

The same review uses the term mitochondrial-derived peptides for short chains coded in that DNA. It names three types: humanin, MOTS-c and six small humanin-like peptides, SHLP1 to SHLP6. MOTS-c comes from the 12S ribosomal RNA gene. Humanin and the six SHLPs come from the 16S ribosomal RNA gene.

SS-31 sits in a separate group. It is a lab-made peptide that collects inside mitochondria. Its drug name is elamipretide. One group is named for where a peptide comes from; the other, for where it goes.

What humanin is and how many amino acids it has

Researchers in Japan reported humanin in 2001. They searched for a gene that protected nerve cells grown in dishes. The cells were dying from inherited Alzheimer's disease genes or from amyloid beta, a protein linked to that disease.

The reviewed UniProt record lists humanin as 24 amino acids. It adds a caution about that count. If mitochondria built the chain with their own genetic code, it would stop three amino acids early, at 21. The record says how cells make and release humanin remains unclear.

A 2009 study found 13 places in nuclear DNA with code similar to the humanin gene. Nuclear DNA is the cell's main DNA, kept in the nucleus. At least ten of these places were active in human tissues. UniProt says the active humanin may come from one of these nuclear copies.

How strong is the evidence? The discovery work tested humanin in nerve cells in dishes. The sources reviewed for this post do not include a study that gave humanin to people.

What MOTS-c is and what FDA found in 2026

A 2015 study named MOTS-c, a 16-amino-acid peptide coded in the 12S ribosomal RNA gene. Insulin resistance means the body responds less to insulin. In mice, MOTS-c treatment prevented insulin resistance linked to age and a high-fat diet. It also prevented weight gain from that diet in those mice.

The reviewed UniProt record adds a caution about how MOTS-c is made. Under the mitochondrial genetic code, its gene has a start signal right beside a stop signal. The record says the chain must therefore be built outside mitochondria, in the cell's fluid. How cells make and release it remains unclear.

FDA reviewed MOTS-c for a compounding advisory meeting on July 23 and 24, 2026. Its briefing says published animal studies of MOTS-c effects used rodents only. FDA did not identify clinical studies that gave MOTS-c to people. In one lab test, human blood quickly cut MOTS-c into shorter pieces. The briefing says FDA's final decision follows the committee process.

CohBar, a company, tested CB4211, which a 2024 review calls a MOTS-c analog. An analog is a changed version of a molecule. The registry lists a phase 1 trial with 88 people, including people with fatty liver disease. It lists the trial as completed in April 2021, with no posted results as of October 30, 2026.

How strong is the evidence? Insufficient. FDA found no published human studies of MOTS-c given as a drug. That finding covers MOTS-c itself; the CB4211 analog is a different molecule without posted results.

What the six small humanin-like peptides are

A 2016 study searched the 16S gene region by computer and found six more short peptides. The authors named them small humanin-like peptides, SHLP1 to SHLP6. In cell tests, SHLP2 and SHLP3 lowered cell death and reactive oxygen species. Reactive oxygen species are unstable molecules that can damage cells.

The same study infused SHLP2 or SHLP3 into the brains of rats during clamp tests. The figure lists six rats. A clamp test holds blood sugar steady while researchers measure how the body handles it. SHLP2 raised glucose uptake and lowered glucose release from the liver.

Blood SHLP2 levels were lower in old mice than in young mice. Four authors listed consulting work and stock in CohBar, the sponsor named on the CB4211 trial. How strong is the evidence? The study tested SHLPs in cells, rats and mice only. It does not show an effect in people.

What natural blood levels in people can show

A 2021 randomized study in Sweden measured natural humanin and MOTS-c in 30 people. Groups of 10 did one cycling session, one leg-strength session or no exercise. Blood humanin rose after cycling. MOTS-c showed only a trend toward rising.

The study found that blood levels did not track fitness measures. At rest, higher humanin went with older age in that group. The humanin UniProt record says its levels decline with age. The MOTS-c record says blood levels fall with age, while muscle levels rise. The sources differ, and the reviewed records do not settle the age pattern.

This study measured the body's own peptides. Nobody received humanin or MOTS-c as a product. A changed blood level does not show that taking the peptide would help. That result applies to 30 people, one exercise session and three hours of follow-up.

What SS-31 is, according to the Forzinity label

FDA's substance record lists SS-31 and elamipretide as names for the same peptide. The Forzinity label, revised September 2025, lists elamipretide as its active ingredient. The label gives the sequence as D-Arg-2,6-dimethyl-Tyr-Lys-Phe-NH2. That is four amino acids, with an amide cap at the end.

Two of those units are unusual. The arginine is the D form, a mirror-image version of the usual building block. The tyrosine carries two extra methyl groups, small carbon-and-hydrogen add-ons. A 2004 lab paper described peptides built on this pattern of alternating ring-shaped and positively charged units.

In that paper, the peptides entered cells and collected 1,000-fold in the inner membrane of mitochondria. The tests used cells, isolated mitochondria and an isolated heart. That result applies to laboratory models only.

The label calls elamipretide a mitochondrial cardiolipin binder. Cardiolipin is a fat in the inner membrane of mitochondria. FDA granted accelerated approval on September 19, 2025, for one use. That use is improving muscle strength in people with Barth syndrome who weigh at least 30 kg.

FDA describes Barth syndrome as a rare, serious and life-threatening disease of the mitochondria. The approval rests on knee muscle strength, an intermediate measure. Continued approval may depend on a confirmatory trial.

The label describes a 12-week crossover trial in 12 people age 12 or older. Forzinity did not beat placebo on its main goals, walking distance and fatigue. Knee strength did not rise during that trial. It rose later in an open-label extension that 10 people entered, where everyone knew they received the drug.

How strong is the evidence? Established for that one product and use: FDA approved it based on the knee strength results. The approval does not extend to other diseases, healthy people or other SS-31 products.

How the label record compares with a seller's claim

Consider a hypothetical listing that calls MOTS-c an FDA-approved mitochondrial peptide. The records reviewed here do not support that claim. FDA approved Forzinity, which contains elamipretide, for Barth syndrome. MOTS-c is a different molecule, and FDA found no published human studies of it given as a drug.

The list below sums up each named peptide. Evidence for one peptide applies to that peptide only.

• Humanin: 24 amino acids, coded in the 16S gene and first studied in nerve cells in dishes. Its source gene is still debated.
• MOTS-c: 16 amino acids, coded in the 12S gene. FDA found no published human studies of it given as a drug.
• SHLP2 and SHLP3: coded in the 16S gene and tested in cells, rats and mice. The study reports no results in people.
• CB4211: tested in a phase 1 trial that enrolled 88 people, including a placebo group. A 2024 review calls the trial drug a MOTS-c analog, and no results are posted.
• Elamipretide (SS-31): four amino acids, two of them modified. Forzinity's approval covers one product and one use.