Mitochondrial Peptides Explained: MOTS-c, SS-31, Humanin and More

“Mitochondrial peptides” is one of the fastest-growing searches in peptide research, and it covers two very different ideas that are often mixed up. The first is a family of peptides that the mitochondria make themselves, from their own tiny genome, and use to send messages to the rest of the body. The second is a group of peptides designed in laboratories to travel into mitochondria and protect them. Both are among the most exciting areas of modern biology, and both have produced molecules that researchers now study around the world.

This guide explains the two kinds of mitochondrial peptide, how each was discovered, what the key members do, what the research has found and how researchers use them. It is an educational overview of research findings, not medical advice. Research compounds mentioned are supplied by Crown Peptides for laboratory research use only.

The Short Answer

Mitochondrial peptides fall into two groups. Mitochondrial-derived peptides, such as humanin, MOTS-c and the small humanin-like peptides, are made from instructions in mitochondrial DNA and act as signals, influencing metabolism, cell survival and stress responses in the cell and throughout the body. Mitochondria-targeted peptides, such as SS-31, are synthetic peptides designed to enter mitochondria and protect their structure and function. The first group are natural messengers; the second are engineered protectors.

First, a Word About Mitochondria

The power stations with their own DNA

Mitochondria are the structures inside cells that turn fuel into energy. Unusually, they carry their own DNA, a small circular genome of about 16,500 DNA letters, separate from the DNA in the cell nucleus. This is a legacy of their origin: mitochondria are thought to descend from bacteria that were engulfed by an ancestral cell more than a billion years ago.

A genome thought to be fully mapped

For decades, the mitochondrial genome was thought to contain just 37 genes: 13 for proteins of the energy machinery, and 24 for the RNA molecules needed to make them. It was considered completely understood. The discovery of mitochondrial-derived peptides showed that it contained hidden messages nobody had noticed.

Inherited from the mother

Mitochondrial DNA is inherited almost entirely from the mother, so the mitochondrial-derived peptides a person carries are passed down the maternal line.

How Mitochondria Came to Live in Our Cells

The idea that mitochondria were once free-living bacteria was championed in the 1960s by the American biologist Lynn Margulis. It was controversial at first but is now widely accepted, supported by the fact that mitochondria have their own circular DNA, their own ribosomes that resemble bacterial ones, and double membranes. Over hundreds of millions of years, most of the original bacterial genes moved into the cell’s nucleus, leaving a small genome behind. That history is what makes mitochondrial-derived peptides so remarkable: they are messages written in the last remnants of an ancient partnership, still being used to coordinate the cell and the body.

A Timeline of Discovery

In 2001, humanin was discovered in Japan while searching for Alzheimer’s-protective factors. Through the 2000s, research showed it protected many cell types and influenced metabolism. In the early 2000s, SS-31 emerged from Szeto and Schiller’s work as a peptide that concentrates in mitochondria. In 2015, MOTS-c was discovered in Los Angeles, the first mitochondrial-derived peptide shown to regulate whole-body metabolism. In 2016, the small humanin-like peptides were described. In 2018, MOTS-c was shown to enter the nucleus and regulate genes. In 2021, MOTS-c was linked to physical performance in ageing mice and to exercise in people, and a genetic variant was linked to diabetes. In 2025, SS-31, as elamipretide, became an approved medicine for Barth syndrome. In little more than two decades, mitochondrial peptides went from an unexpected finding to a major field.

Group One: Mitochondrial-Derived Peptides

Humanin: the first discovery

The story began in 2001, when Japanese researchers led by Ikuo Nishimoto, searching for molecules that protect neurons from Alzheimer’s disease-related damage, found a small peptide they named humanin. Their paper in the Proceedings of the National Academy of Sciences described it as a rescue factor that abolished neuronal death caused by a wide range of Alzheimer’s disease genes and by amyloid beta (PMID: 11371646, PMC33469). Remarkably, its code appeared to sit within a mitochondrial gene for ribosomal RNA, a region thought to make only structural RNA, not peptides.

MOTS-c: the metabolic messenger

In 2015, Changhan Lee, Pinchas Cohen and colleagues at the University of Southern California searched the mitochondrial genome for other hidden peptides and found MOTS-c, a 16-amino-acid peptide encoded within the gene for 12S ribosomal RNA. In Cell Metabolism, they showed that it targeted skeletal muscle, activated AMPK, the cell’s energy sensor, and prevented age-dependent and diet-induced insulin resistance and obesity in mice (PMID: 25738459, PMC4350682).

Three years later, the same group found that under metabolic stress, MOTS-c moves into the cell nucleus and regulates nuclear genes, including antioxidant genes (PMID: 29983246, PMC6185997), a striking example of the mitochondrial genome communicating with the nuclear genome. In 2021, they reported that MOTS-c enhanced physical performance in young, middle-aged and old mice, and that exercise raises MOTS-c levels in human muscle and blood (PMID: 33473109, PMC7817689). A naturally occurring variant of MOTS-c, found mainly in people of East Asian ancestry, was linked to type 2 diabetes in less active men (PMID: 33468709, PMC7880332).

Crown Peptides supplies MOTS-c; our MOTS-c guide covers its research in depth.

Humanin after its discovery

After its initial discovery as a neuron-protecting factor, humanin was found to act on several receptors on the cell surface and on proteins inside cells that control cell death. Research in animals linked it to insulin sensitivity, protection of the heart and blood vessels, and resistance to stress. Its levels were reported to decline with age in several studies, and humanin variants and analogues have been developed to explore its effects further. It remains one of the most studied mitochondrial-derived peptides and was the proof that mitochondrial DNA could encode signalling molecules at all.

The small humanin-like peptides

In 2016, Cobb, Cohen and colleagues reported in Aging a further family: small humanin-like peptides, SHLP1 to SHLP6, also encoded within the mitochondrial 16S ribosomal RNA gene (PMID: 27070352, PMC4925829). They found these peptides differed in their effects, with some, such as SHLP2 and SHLP3, influencing cell survival, insulin sensitivity and inflammatory markers, and that their levels changed with age.

What they have in common

A 2021 review in GeroScience surveyed mitochondrial-derived peptides in ageing and age-related disease, describing them as a new class of signalling molecules linking mitochondrial function to health across the body (PMID: 32910336, PMC8190245). Many circulate in the blood, respond to stress and exercise, and change with age, which is why researchers sometimes call them mitokines: mitochondrial hormones.

Group Two: Mitochondria-Targeted Peptides

The challenge of getting inside

Mitochondria are surrounded by two membranes, and the inner one is one of the most impermeable barriers in the cell. Getting molecules inside is difficult, which has long limited attempts to protect mitochondria directly.

SS-31: the leading example

SS-31, developed by Hazel Szeto and Peter Schiller, is a four-building-block synthetic peptide that crosses membranes and concentrates at the inner mitochondrial membrane, where it binds cardiolipin, a lipid essential to the energy machinery. A 2014 review in the British Journal of Pharmacology described it as a first-in-class cardiolipin-protective compound (PMID: 24117165, PMC3976620). Its clinical form, elamipretide, received accelerated US approval in September 2025 for Barth syndrome. Crown Peptides supplies SS-31 in 10mg and 50mg formats; see Elamipretide and our SS-31 guide.

How targeted peptides differ from natural ones

Mitochondria-targeted peptides do not carry messages. They are designed to act as physical protectors, stabilising membranes and reducing the leakage of harmful reactive oxygen species. They are tools for fixing mitochondria, rather than signals mitochondria send.

Natural Messengers vs Engineered Protectors

Origin

Mitochondrial-derived peptides are made by the body from mitochondrial DNA. Mitochondria-targeted peptides are designed and made synthetically.

Where they act

Mitochondrial-derived peptides often leave the mitochondria, travel through the blood and act on other cells and tissues, or enter the nucleus, as MOTS-c does. Mitochondria-targeted peptides act inside the mitochondria themselves.

What they do

Mitochondrial-derived peptides regulate metabolism, cell survival and stress responses. Mitochondria-targeted peptides protect mitochondrial structure and function.

Clinical status

SS-31 has reached approval as a medicine for one condition. Mitochondrial-derived peptides remain research compounds, though analogues of MOTS-c and humanin have been explored in early development.

What About “Mitochondrial Peptide Supplements”?

Searches for mitochondrial peptide supplements are common, and products are marketed with that label. It is worth being clear. Research compounds such as MOTS-c and SS-31 are not dietary supplements, and peptides generally do not survive digestion well. Claims that a supplement contains mitochondrial peptides or boosts them should be judged against evidence, including independent testing of what the product contains. Crown Peptides supplies these compounds for laboratory research only.

Mitochondrial Peptides and Exercise

One of the most intriguing findings about mitochondrial-derived peptides is their link to exercise. The 2021 MOTS-c study found that exercise raises MOTS-c levels in human skeletal muscle and in the blood, suggesting it may be one of the molecules through which exercise produces its benefits. Because exercise is the most powerful known intervention for mitochondrial health, research on mitochondrial peptides is partly an attempt to understand how exercise talks to the body at a molecular level, and whether that conversation can be studied, or even mimicked, in the laboratory.

Why the Discovery Surprised Scientists

The mitochondrial genome is one of the most intensively studied pieces of DNA in biology. It was fully sequenced in 1981, and its genes were thought to be completely catalogued. Finding previously unknown peptides hidden within ribosomal RNA genes, genes believed to make only structural RNA, was a genuine surprise. It showed that even the best-studied genomes can hide functions, and it encouraged researchers to search for small hidden peptides in the nuclear genome too, a search that has since found many more.

Why Mitochondrial Peptides Matter for Ageing Research

Mitochondrial dysfunction is one of the central hallmarks of ageing. Mitochondria become less efficient, leak more reactive oxygen species and communicate less effectively with the rest of the cell. Mitochondrial-derived peptides offer a window onto that communication: several decline with age, and restoring them has improved age-related measures in animals. Mitochondria-targeted peptides offer a way to test whether protecting the machinery itself slows decline. Together, they give researchers tools for both sides of mitochondrial ageing. Our longevity research guide places them in that wider context.

Measuring Mitochondrial Peptides in the Body

Because several mitochondrial-derived peptides circulate in the blood, researchers can measure them, typically with antibody-based assays or mass spectrometry. Studies have measured MOTS-c and humanin in people of different ages, in people with metabolic conditions and before and after exercise. These measurements have limitations: levels can vary with time of day, recent activity and the assay used, and blood levels may not reflect what is happening inside tissues. Even so, they have provided some of the first human evidence linking mitochondrial peptides to ageing and metabolism.

How the Two Groups Might Complement Each Other

The two groups of mitochondrial peptides act at different levels. SS-31 protects the physical machinery inside mitochondria. MOTS-c and its relatives act as signals that adjust how the cell and body respond to energy demands. In principle, a damaged mitochondrion may both produce energy poorly and send weaker signals, so protecting the machinery might also influence signalling. Studying a mitochondria-targeted peptide alongside a mitochondrial-derived one, with each also tested alone, would help reveal how structure and signalling interact.

Sex Differences in Mitochondrial Peptide Research

Several findings suggest mitochondrial peptides may behave differently in males and females. The MOTS-c variant was linked to diabetes in men but not women, and in mouse experiments the variant’s effects were seen only in males. Hormones influence mitochondrial function, and mitochondrial DNA is inherited only through the mother. Including both sexes and analysing them separately is therefore especially important in this field.

What the Research Still Needs

The field has advanced quickly, but important gaps remain. Controlled human trials of mitochondrial-derived peptides are lacking. The receptors through which several of them act are not fully identified. How their levels are controlled, and why they change with age, is still being worked out. And independent replication of key findings across laboratories will strengthen confidence. Each gap is also an opportunity for researchers entering the field.

Designing Research With Mitochondrial Peptides

Match the compound to the question

For questions about metabolic signalling, insulin sensitivity or exercise-like effects, MOTS-c is the natural tool. For questions about mitochondrial membrane integrity and reactive oxygen species, SS-31 fits. Comparing them in the same model shows whether signalling or structure matters more.

Measure mitochondrial function directly

Oxygen consumption, ATP production, membrane potential, reactive oxygen species and mitochondrial structure are the core readouts.

Measure systemic effects

Because mitochondrial-derived peptides act across the body, measures such as blood sugar, insulin sensitivity, body composition and exercise capacity are important.

Consider sex and genetics

The MOTS-c variant study found effects in men but not women, and genetics shaped responses. Including both sexes and considering genetic background strengthens any study.

Common Misconceptions

“All mitochondrial peptides are the same”

They are very different. Humanin, MOTS-c and the SHLPs are natural signals with distinct effects; SS-31 is a synthetic protector.

“They are energy boosters”

Their effects are more subtle than simply increasing energy. MOTS-c regulates metabolism and stress responses; SS-31 protects membrane structure; humanin influences cell survival.

“More research has been done in people than animals”

Apart from SS-31’s clinical trials, most research on mitochondrial-derived peptides has been in cells and animals, with human data mainly observational, such as measuring levels with age or exercise.

Where the Field Is Heading

Research on mitochondrial peptides is moving in several directions. Scientists are searching for more hidden peptides in mitochondrial DNA. They are working out how these peptides are made, released and recognised by other cells. They are studying how natural genetic variants in mitochondrial DNA, such as the MOTS-c variant, influence health across populations. And they are developing more stable analogues for research. The field is young, fast-moving and full of open questions, which is exactly what makes it so attractive to researchers.

The Technical Breakdown

How a peptide can hide in ribosomal RNA

Humanin, MOTS-c and the SHLPs are encoded by short open reading frames within mitochondrial ribosomal RNA genes, stretches that can in principle be read into short peptides. How they are translated is still being worked out; one possibility is translation in the cytoplasm using the standard genetic code rather than the slightly different mitochondrial code.

AMPK and MOTS-c

MOTS-c inhibits the folate cycle, causing a build-up of AICAR, which activates AMPK. AMPK increases glucose uptake and fat burning, mimicking some effects of exercise.

SS-31 and cardiolipin

SS-31’s alternating positive charges and aromatic rings allow it to concentrate at the inner membrane, where it binds cardiolipin, stabilising cristae and the electron transport chain.

Mitokines

Mitokines are signals released in response to mitochondrial stress that act on other cells or tissues. Mitochondrial-derived peptides are among the best-studied examples, alongside proteins such as FGF21 and GDF15.

Handling Mitochondrial Peptides

MOTS-c and SS-31 are supplied as freeze-dried powders and should be stored cold, dry and away from light. MOTS-c’s methionines and tryptophan make it prone to oxidation, so limiting air exposure and preparing fresh solutions is sensible. For longer studies, using a single batch throughout avoids variation between batches, and SS-31’s 50mg format makes that easier. Our guides to how long peptides last and the peptide calculator cover the practical details, and Bacteriostatic Water is available alongside.

Other Molecules That Talk to Mitochondria

Mitochondrial peptides are not the only molecules in this conversation. NAD+ fuels the mitochondrial sirtuin SIRT3. Methylene Blue can accept and donate electrons within the energy chain. L-Carnitine carries fats into mitochondria to be burned. 5-Amino-1MQ protects the NAD+ supply. Glutathione defends against the reactive oxygen species mitochondria produce. Studying mitochondrial peptides alongside these compounds lets researchers explore how signalling, structure, fuel supply and protection fit together.

Why Researchers Find the Field So Exciting

Mitochondrial peptides combine several things researchers value. They are rooted in a well-understood organelle, yet reveal functions nobody expected. They connect cellular energy to whole-body health, ageing and exercise. They include both natural signals, which illuminate how the body regulates itself, and engineered tools, which let researchers test interventions directly. And one of them, SS-31, has already made the journey from laboratory to approved medicine, showing that the field can deliver practical results as well as insight.

Why Quality Matters

MOTS-c’s 16 amino acids include two methionines and a tryptophan, which can oxidise. SS-31 contains a D-amino acid and dimethyltyrosine, which must be exactly right. Every batch supplied by Crown Peptides comes with a batch-specific certificate of analysis showing HPLC purity and mass spectrometry identity. Published certificates are on our Lab Reports page, and our guides to peptide testing and reconstitution cover the practical side.

Related Compounds and Reading

Other compounds used in mitochondrial research include NAD+, Methylene Blue, L-Carnitine and 5-Amino-1MQ. Read SS-31 vs NAD+, SS-31 vs MOTS-c and NAD+ vs MOTS-c, and browse the ageing and cellular research peptides category.

Mitochondrial Peptides: Questions, Answered

What are mitochondrial peptides?

Either peptides made from mitochondrial DNA that act as signals, such as humanin and MOTS-c, or synthetic peptides designed to protect mitochondria, such as SS-31.

What is a mitochondrial-derived peptide?

A peptide encoded in mitochondrial DNA. Humanin, discovered in 2001, was the first; MOTS-c and the SHLPs followed.

Is SS-31 a mitochondrial-derived peptide?

No. SS-31 is a synthetic mitochondria-targeted peptide, designed in a laboratory to enter mitochondria and bind cardiolipin.

Do mitochondrial peptides decline with age?

Research has found age-related changes in several mitochondrial-derived peptides, including lower circulating MOTS-c and changes in SHLPs.

Where do mitochondrial-derived peptides act?

Many leave the mitochondria and act elsewhere in the cell or travel through the blood to other tissues. MOTS-c can even enter the nucleus under metabolic stress and regulate genes there.

Why is humanin called humanin?

Its name is often explained as reflecting the discoverers’ hope that it might help preserve the humanity that Alzheimer’s disease takes away, since it was found while searching for factors that protect neurons from Alzheimer’s-related damage.

What are the SHLPs?

Small humanin-like peptides, a family of six peptides encoded in the mitochondrial 16S ribosomal RNA gene, described in 2016. Some influence cell survival, insulin sensitivity and inflammation.

Are mitochondrial peptides legal in the UK?

MOTS-c and SS-31 are not controlled drugs in the UK and are supplied as research materials. See are peptides legal in the UK.

What is the most studied mitochondrial peptide?

Among natural ones, humanin and MOTS-c have the largest research bases. Among synthetic ones, SS-31, which has reached clinical approval as elamipretide.

Where can I read the studies?

Every study in this guide is linked to its PubMed record, where the abstract and often the full paper can be read.

What sizes is SS-31 available in?

Crown Peptides supplies SS-31 in 10mg and 50mg formats for laboratory research.

How is humanin different from MOTS-c?

Humanin was discovered as a neuron-protecting factor and is studied mainly for cell survival; MOTS-c is studied mainly for metabolism, muscle and exercise.

Can mitochondrial peptides be measured in blood?

Yes, several circulate and can be measured, though levels vary with time of day, activity and assay, and may not reflect tissue levels.

What is a mitokine?

A signal released in response to mitochondrial stress that acts on other cells or tissues. Mitochondrial-derived peptides are among the best-known examples.

Who discovered MOTS-c?

Changhan Lee, Pinchas Cohen and colleagues at the University of Southern California, in 2015.

Why is mitochondrial DNA inherited from the mother?

Because the egg supplies the mitochondria to the embryo, while the sperm’s few mitochondria are normally eliminated.

Does exercise affect mitochondrial peptides?

Research has found that exercise raises MOTS-c levels in human muscle and blood.

Are mitochondrial peptides supplements?

Research compounds such as MOTS-c and SS-31 are not dietary supplements, and Crown Peptides supplies them for laboratory research only.

Messages From the Power Station

For most of biology’s history, mitochondria were seen as silent engines. The discovery of mitochondrial-derived peptides revealed that they speak, sending messages that shape metabolism and survival throughout the body. The development of mitochondria-targeted peptides showed that they can also be protected directly. From humanin and MOTS-c to SS-31, these molecules have turned the mitochondrion into one of the most exciting frontiers in peptide research. There is still far more to learn: hidden peptides to be found, receptors to be identified and human studies to be run. For researchers entering the field now, that makes mitochondrial peptides one of the richest and most rewarding areas in the whole of modern biology to explore.

Explore MOTS-c and SS-31 from Crown Peptides, every batch HPLC and mass spectrometry verified and dispatched from the UK.