MOTS-c: Mitochondrial-Derived Peptide Profile

In 2015, a research team at the University of Southern California made a discovery that changed how scientists think about mitochondria. These organelles — the tiny power plants inside your cells — weren't just generating energy. They were sending instructions. Specifically, they were producing a small peptide, just 16 amino acids long, that could travel through the cell, enter the nucleus, and reprogram gene expression in response to metabolic stress.

That peptide is MOTS-c.

Short for Mitochondrial Open Reading Frame of the 12S rRNA Type-C, MOTS-c has since become one of the most studied molecules in metabolic and aging research. It acts as a kind of metabolic messenger — a signal from your mitochondria to the rest of your body that says "adapt." In mice, it prevents obesity on a high-fat diet, reverses age-related insulin resistance, and doubles running capacity in old animals. In humans, it rises naturally during exercise, earning it the label "exercise mimetic." And circulating levels drop steadily with age, which has researchers asking whether restoring MOTS-c could slow metabolic decline.

But the gap between animal studies and approved human therapies remains wide. No completed clinical trials of MOTS-c exist in humans. The FDA has not approved it for any medical use. And athletes should know that WADA explicitly added it to the prohibited list in 2024. Here's what the science actually shows — and where it still falls short.

Quick Facts
What Is MOTS-c?
Discovery and the Mitochondrial-Derived Peptide Revolution
How MOTS-c Works: Mechanisms of Action
Research Evidence
The First Near-Human Trial: CB4211
Administration and Dosing
Safety Profile and Side Effects
Legal and Regulatory Status
Limitations of Current Research
Frequently Asked Questions
The Bottom Line

Quick Facts

Property	Details
Full name	MOTS-c (Mitochondrial Open Reading Frame of the 12S rRNA Type-C)
Type	Mitochondrial-derived peptide (MDP)
Length	16 amino acids
Encoded by	Small open reading frame (sORF) in the mitochondrial 12S rRNA gene (positions m.1343–m.1393)
Discovered	2015 by Changhan Lee, Pinchas Cohen, and colleagues at USC
Primary mechanism	AMPK activation via folate-methionine cycle inhibition; nuclear translocation under stress
Other reported effects	Insulin sensitization, exercise mimetic, anti-obesity, anti-inflammatory, myostatin reduction
Notable polymorphism	m.1382A>C (K14Q variant), found in Northeast Asian populations
FDA status	Not approved for any human use; not permitted for compounding
WADA status	Prohibited at all times (added explicitly in 2024, Section 4.4.1 — AMPK activators)
Research status	Strong preclinical data; no completed human clinical trials of native MOTS-c

What Is MOTS-c?

MOTS-c is a 16-amino-acid peptide produced from instructions encoded in your mitochondrial DNA — not your nuclear DNA. That distinction matters. For decades, scientists assumed mitochondrial DNA's only job was making the 13 proteins needed for oxidative phosphorylation (the process mitochondria use to generate ATP). The discovery of MOTS-c, along with the earlier discovery of humanin, proved that assumption wrong. Mitochondria are also producing signaling molecules that regulate metabolism, stress responses, and gene expression across the entire cell.

MOTS-c is translated in the cytoplasm (not inside the mitochondria) from a polyadenylated transcript exported from the mitochondrial genome. Under normal, resting conditions, it associates primarily with mitochondria. But when the cell faces metabolic stress — glucose restriction, oxidative pressure, or exercise — MOTS-c moves into the nucleus, where it directly binds DNA and works alongside transcription factors to activate protective genes.

The peptide circulates in blood plasma, making it technically a hormone — or more precisely, a "mitokine," a signaling molecule produced by mitochondria that acts on distant tissues. Its primary target organ appears to be skeletal muscle, though researchers have detected it in multiple tissues throughout the body.

What makes MOTS-c particularly interesting is its functional overlap with exercise. It activates many of the same metabolic pathways that physical activity does, which is why some researchers call it a natural "exercise pill" encoded directly in the mitochondrial genome.

Discovery and the Mitochondrial-Derived Peptide Revolution

The story starts with humanin, a 24-amino-acid peptide discovered in 2001 by Hashimoto and colleagues. They cloned it from the brain of an Alzheimer's disease patient and found it protected neurons against amyloid-beta toxicity. The surprise: it was encoded in mitochondrial DNA, within the 16S rRNA gene. That was not supposed to happen — the prevailing view held that mitochondrial DNA only coded for structural proteins of the electron transport chain.

Humanin's discovery raised an obvious question: if one signaling peptide was hiding in mitochondrial DNA, were there more?

The answer came from Pinchas Cohen's lab at the USC Leonard Davis School of Gerontology. His team conducted systematic bioinformatic searches of the mitochondrial genome, looking for additional small open reading frames (sORFs) that might encode functional peptides. In the 16S rRNA region alone, they found six — the small humanin-like peptides, or SHLPs 1 through 6.

Then, in March 2015, postdoctoral researcher Changhan Lee identified a sORF in the 12S rRNA gene. The 51-base-pair sequence encoded a 16-amino-acid peptide that, when synthesized and injected into mice, had dramatic metabolic effects. They named it MOTS-c. The landmark paper, published in Cell Metabolism, showed MOTS-c could prevent diet-induced obesity and improve insulin sensitivity in mice — and it did so primarily by acting on skeletal muscle through AMPK activation.

To date, eight mitochondrial-derived peptides have been characterized: humanin, MOTS-c, and SHLPs 1–6. Together, they've redefined mitochondria from passive energy factories into active signaling hubs that co-regulate nuclear gene expression. Cohen has described this as evidence that the mitochondrial and nuclear genomes "co-evolved to independently encode for factors to cross-regulate each other." MOTS-c, as the most metabolically potent member of this family, has attracted the most research attention.

How MOTS-c Works: Mechanisms of Action

MOTS-c operates through a multi-step signaling cascade that connects mitochondrial metabolism to nuclear gene regulation. Here's how the pathway unfolds.

Step 1: Disrupting the Folate-Methionine Cycle

When Lee's team first profiled MOTS-c's cellular effects using unbiased metabolomics, they found it targets the folate-methionine cycle — a metabolic pathway that feeds one-carbon units into DNA synthesis and methylation reactions. MOTS-c treatment decreased levels of 5-methyltetrahydrofolate (5Me-THF) and methionine while increasing homocysteine. The folate cycle disruption came first, suggesting that's the initial point of intervention.

Step 2: AICAR Accumulation and AMPK Activation

The folate cycle is directly tethered to de novo purine biosynthesis. When MOTS-c blocks this pathway, levels of AICAR (5-aminoimidazole-4-carboxamide ribonucleotide) build up inside the cell. AICAR is a well-known AMPK activator — in fact, it works through a similar mechanism to metformin, one of the most widely prescribed diabetes drugs in the world.

MOTS-c treatment increases phosphorylation of AMPKalpha at Thr172 in a time- and dose-dependent manner. Downstream, this triggers increased fatty acid oxidation via ACC phosphorylation and CPT-1 upregulation, and increased glucose uptake via GLUT4 translocation to the cell surface — primarily in skeletal muscle.

However, AMPK knockdown experiments showed that AMPK activation accounts for only part of MOTS-c's effects. Knocking down AMPKalpha2 reduced MOTS-c's glycolytic boost by about 16%; knocking down both AMPKalpha1 and alpha2 reduced it by 30%. This means MOTS-c works through AMPK, but also through additional pathways not yet fully mapped.

Step 3: Nuclear Translocation

This is the part that surprised researchers the most. In a 2018 study published in Cell Metabolism, Kim, Son, Benayoun, and Lee showed that under metabolic stress, MOTS-c physically moves from the cytoplasm into the nucleus. This translocation depends on AMPK activation and is accompanied by increased reactive oxygen species (ROS).

Once in the nucleus, MOTS-c directly binds DNA — specifically, promoter regions containing antioxidant response elements (AREs). Using electrophoretic mobility shift assays, the researchers demonstrated that MOTS-c binds the promoters of NRF2 target genes, including HO-1, NQO1, and GPX2. Two structural motifs in the MOTS-c peptide are required: the hydrophobic core (YIFY, positions 8–11) for DNA binding, and the basic tail (RKLR, positions 13–16) also for DNA interaction.

MOTS-c also physically interacts with the transcription factor NRF2 (NFE2L2), a master regulator of cellular antioxidant defenses. Notably, MOTS-c and NRF2 translocate to the nucleus independently of each other — they meet and cooperate once both arrive.

The Net Effect

The combined result is a coordinated stress response: MOTS-c senses metabolic pressure through its effects on one-carbon metabolism, activates AMPK to shift cellular energy balance toward glucose utilization and fat burning, then moves into the nucleus to activate protective gene programs. It's a direct communication line from the mitochondrial genome to the nuclear genome — what researchers call "mitonuclear communication."

Research Evidence

Metabolic Syndrome and Obesity

The original 2015 Cell Metabolism paper established MOTS-c as a metabolic regulator. Eight-week-old male CD-1 mice were fed a high-fat diet (60% calories from fat) and treated with MOTS-c at 0.5 mg/kg/day via intraperitoneal injection for eight weeks. The treated mice did not become obese despite eating the same number of calories as controls. They showed less hepatic fat accumulation, lower insulin levels, and increased heat production — suggesting higher energy expenditure.

The same effects held in a second mouse strain (C57BL/6), ruling out strain-specific artifacts. A 2019 follow-up study using metabolomics showed that MOTS-c treatment lowered plasma metabolites in three independent pathways — sphingolipid metabolism, monoacylglycerol metabolism, and dicarboxylate metabolism — all of which are elevated in metabolic syndrome.

For readers interested in other peptides studied for metabolic applications, see our guides on semaglutide and AOD-9604, as well as best peptides for fat loss.

Exercise Physiology

The most striking MOTS-c research came in January 2021, when Reynolds, Lee, and colleagues published a study in Nature Communications showing that MOTS-c treatment dramatically improved physical performance in mice across all age groups.

Young mice (2 months), middle-aged mice (12 months), and old mice (22 months) all showed improved running capacity after acute MOTS-c treatment. The old mice were particularly remarkable — they doubled their running distance on a treadmill and even outperformed untreated middle-aged mice.

Even more impressive: when the researchers initiated intermittent MOTS-c treatment (three times per week) in mice at 23.5 months of age — roughly equivalent to humans in their late 70s — the treated mice showed improved grip strength, longer stride length, and better physical performance on walking tests.

In humans, the same study measured MOTS-c levels in skeletal muscle and blood during exercise. Muscle MOTS-c levels increased nearly 12-fold during exercise, with plasma levels rising approximately 50%. These levels remained partially elevated four hours after exercise ended.

A 2024 study in Free Radical Biology and Medicine extended these findings to marathon runners versus sedentary individuals, showing a strong correlation between serum MOTS-c levels and aerobic capacity. The authors proposed that endurance training promotes MOTS-c secretion from skeletal muscle, which in turn improves mitochondrial respiratory function through the AMPK/PGC-1alpha pathway.

These exercise-related findings place MOTS-c alongside other peptides studied for athletic performance and mitochondrial health.

Aging and Insulin Sensitivity

MOTS-c levels decline with age in both mice and humans. In mouse studies, circulating MOTS-c drops progressively in skeletal muscle and blood as animals age, coinciding with the development of insulin resistance. Human data shows that blood MOTS-c levels in young adults are roughly 11% higher than in middle-aged adults and 21% higher than in older adults.

Restoring MOTS-c in older mice (12 months) through systemic injection reversed age-dependent skeletal muscle insulin resistance. The hyperinsulinemic-euglycemic clamp technique confirmed that MOTS-c improves insulin sensitivity specifically in skeletal muscle (increasing glucose clearance) rather than in the liver (reducing glucose production).

A 2025 study in Experimental & Molecular Medicine showed that MOTS-c also declines in aging pancreatic islet cells. Treating aged mouse pancreatic islets with MOTS-c reduced cellular senescence and improved glucose intolerance in diabetic mouse models. In humans, circulating MOTS-c was lower in type 2 diabetes patients than in healthy controls.

For broader context on peptides in longevity research, see Epitalon and the best peptides for anti-aging and longevity guide.

The K14Q Variant and the Longevity Paradox

A naturally occurring mtDNA polymorphism (m.1382A>C) causes a lysine-to-glutamine substitution at position 14 of the MOTS-c peptide, creating the K14Q variant. This variant is specific to Northeast Asian populations and is part of mitochondrial haplogroup D4b2 — a haplogroup associated with exceptional longevity in Japanese centenarians.

But there's a twist. A meta-analysis of three cohorts (n = 27,527) showed that men carrying the C-allele had higher rates of type 2 diabetes — but only if they were physically inactive. Men in the highest third of physical activity showed no increased diabetes risk. A 2024 study confirmed that K14Q MOTS-c has more than 10-fold weaker binding to casein kinase 2 alpha (CK2alpha), one of its direct molecular targets. In high-fat-diet mice, wild-type MOTS-c improved glucose tolerance; the K14Q variant did not.

This creates a paradox: the same variant linked to longevity is also linked to metabolic disease. The likely resolution is that the K14Q variant pushes carriers toward physical activity for metabolic health — a "use it or lose it" genetic nudge that may have provided a selective advantage in historically active populations.

Other Emerging Research Areas

Recent studies have expanded MOTS-c research into new territory:

Cardiovascular protection: MOTS-c prevents heart failure in mice through AMPK pathway activation. A 2025 study showed it restores mitochondrial respiration in type 2 diabetic hearts and delays weight gain in diabetic rats.
Cancer: A 2024 study in Advanced Science found MOTS-c levels were reduced in ovarian cancer patients' serum and tumor tissue. Exogenous MOTS-c inhibited cancer cell proliferation and migration.
Muscle atrophy: MOTS-c reduces myostatin levels — a negative regulator of muscle growth — and attenuates immobilization-induced skeletal muscle atrophy in mice (Kumagai et al., 2024).
Neuroprotection: A 2024 study showed neuroprotective effects after traumatic brain injury in mice.

The First Near-Human Trial: CB4211

No completed clinical trial has tested native MOTS-c in humans. However, CohBar, a biotechnology company co-founded by Pinchas Cohen, developed CB4211 — a synthetic analog of MOTS-c optimized for pharmaceutical use — and took it through a Phase 1a/1b trial (NCT03998514) in patients with nonalcoholic fatty liver disease (NAFLD) and obesity.

Trial Design

The Phase 1a stage enrolled 65 healthy adults in a dose-escalation study to assess safety and tolerability. The Phase 1b stage randomized 20 obese participants (all with at least 10% liver fat by MRI) to receive either 25 mg CB4211 or placebo via daily subcutaneous injection for 28 days.

Results (August 2021)

CB4211 met its primary safety endpoint — no serious adverse events occurred. On exploratory efficacy measures:

Liver enzymes: ALT dropped 25% and AST dropped 17% relative to placebo — both statistically significant.
Glucose levels: Significant decrease in fasting glucose.
Liver fat: MRI-measured liver fat decreased by about 5% in both groups, with no significant difference between CB4211 and placebo.
Body weight: A trend toward lower body weight in the treated group, but not statistically significant after only four weeks.

Setbacks and Discontinuation

The trial faced several interruptions. In 2018, the study was temporarily suspended due to persistent (though painless) injection site reactions — subcutaneous nodules that persisted at injection sites. After protocol amendments and FDA discussions, the Phase 1a resumed in 2019. COVID-19 paused the Phase 1b in early 2020, which completed in April 2021.

Despite the positive liver enzyme data, CohBar ultimately discontinued CB4211 development. The combination of persistent injection site reactions, lack of liver fat reduction versus placebo in a short trial, and the company's broader financial challenges contributed to the decision.

This remains the closest any MOTS-c-based therapy has come to human clinical testing.

Administration and Dosing

No established human dosing protocol exists for MOTS-c. The peptide has not been tested in controlled human clinical trials. The information below comes from animal research and is included for educational context only.

Animal Research Doses

In the original Lee et al. 2015 study, mice received 0.5 mg/kg/day via intraperitoneal injection for 8 weeks. Higher doses (5–15 mg/kg) have been used in shorter-duration studies (2–4 weeks). The Reynolds et al. 2021 Nature Communications study used intermittent treatment (3 times per week) in aged mice to improve physical performance.

A 2023 review in Frontiers in Endocrinology noted that lower doses (0.5–5 mg/kg) were typically administered over 8–12 weeks, while higher doses (10–15 mg/kg) were used in 2–4 week protocols.

Route of Administration

All published animal studies used injection (intraperitoneal in mice). As a 16-amino-acid peptide, MOTS-c would be rapidly degraded in the gastrointestinal tract, making oral administration ineffective. Subcutaneous injection is the route most commonly discussed for potential human use.

Stability and Bioavailability

One of the practical challenges with MOTS-c is bioavailability. A 2025 review in Molecular Medicine Reports noted that mitochondrial-derived peptides generally suffer from low bioavailability, poor stability, and high synthesis costs. Improving drug delivery systems remains a barrier to clinical translation.

Safety Profile and Side Effects

The safety data for MOTS-c is limited. No controlled human safety trial of the native peptide has been completed.

What Animal Studies Show

In published rodent studies, MOTS-c at doses up to 15 mg/kg has not produced reported serious toxicity. The peptide appears well-tolerated in short-term and intermediate-term animal protocols.

What the CB4211 Trial Showed

The closest human data comes from the CohBar CB4211 trial. At 25 mg/day for 28 days, CB4211 was generally well-tolerated with no serious adverse events. However, persistent injection site reactions — painless subcutaneous nodules — were a recurring issue that ultimately contributed to the program's discontinuation.

Unknown Risks

Several gaps remain:

Long-term effects: No study has evaluated chronic MOTS-c administration beyond a few weeks in any species.
Cancer risk: While recent research suggests MOTS-c may suppress certain cancers (ovarian cancer, in the 2024 Advanced Science study), other researchers have raised concerns about its possible role in prostate and breast cancer. This is unresolved.
Supraphysiological dosing: The consequences of chronically elevating MOTS-c levels above what the body produces naturally are unknown.
Drug interactions: No interaction studies have been conducted.

Reported Anecdotal Side Effects

Among individuals who report purchasing MOTS-c online (where it is sold as a "research chemical"), commonly reported side effects include injection site reactions (redness, itching, discomfort), heart palpitations, and mild digestive changes. These reports are unverified and uncontrolled.

Legal and Regulatory Status

United States

MOTS-c is not approved by the FDA for any human use. It is not classified as a dietary supplement ingredient and cannot legally be used in compounded medications. Websites selling MOTS-c typically label it "for research purposes only."

Sports and Anti-Doping

MOTS-c is prohibited at all times under the WADA Prohibited List, Section 4.4.1 (Activators of AMP-activated protein kinase). It was explicitly added as a named example in the 2024 list and remains prohibited on the 2025 and 2026 lists. Athletes cannot obtain a Therapeutic Use Exemption because there is no approved therapeutic use. USADA has specifically warned that MOTS-c is "heavily marketed by wellness and anti-aging clinics" despite being experimental and unapproved.

Other Jurisdictions

No country has approved MOTS-c for therapeutic human use. Regulatory status for research peptides varies by jurisdiction.

Limitations of Current Research

The MOTS-c literature is growing fast, but several significant limitations should inform how you interpret the findings:

No completed human trials of native MOTS-c. Every positive finding — the obesity prevention, the running capacity improvements, the insulin sensitization — comes from mouse models. Animal results frequently fail to translate to humans.
Narrow research groups. Much of the foundational MOTS-c work comes from the Cohen/Lee labs at USC. While the science is rigorous and published in top journals (Cell Metabolism, Nature Communications), independent replication by unrelated groups is still catching up.
Short study durations. Most animal studies run 4–12 weeks. The effects of long-term MOTS-c administration are unstudied.
No dose-response data in humans. Optimal dosing, timing, and duration for any potential human application are completely unknown.
Bioavailability challenges. MOTS-c is a small peptide that may be rapidly cleared from circulation. Effective delivery methods for sustained human dosing have not been established.
The CB4211 program failed. The only MOTS-c analog to reach human testing was discontinued, partly due to injection site issues and partly due to underwhelming efficacy on the primary clinical endpoint (liver fat).
Cancer uncertainty. The relationship between MOTS-c and cancer is not settled. Some studies show tumor suppression; others raise concerns about tumor promotion in hormone-sensitive tissues.
Observational human data has confounders. Studies showing lower MOTS-c in diabetic or obese patients are correlational. Low MOTS-c could be a cause, a consequence, or a bystander of metabolic disease.

Frequently Asked Questions

What does MOTS-c stand for?

MOTS-c stands for Mitochondrial Open Reading Frame of the 12S rRNA Type-C. It refers to a small open reading frame within the 12S ribosomal RNA gene in mitochondrial DNA that encodes a 16-amino-acid peptide.

Is MOTS-c the same as humanin?

No. Both are mitochondrial-derived peptides, but they come from different genes and have different functions. Humanin is a 24-amino-acid peptide encoded by the 16S rRNA gene, primarily studied for neuroprotection and anti-apoptotic effects. MOTS-c is a 16-amino-acid peptide from the 12S rRNA gene, primarily studied for metabolic regulation and exercise-mimetic effects. They belong to the same family of MDPs but target different pathways.

Can MOTS-c replace exercise?

No — at least not based on current evidence. While MOTS-c activates some of the same pathways as exercise (particularly AMPK signaling in skeletal muscle), exercise produces a far broader range of physiological adaptations — cardiovascular, neurological, hormonal, musculoskeletal — that a single peptide cannot replicate. The "exercise mimetic" label reflects overlapping metabolic pathways, not a true substitution. Notably, the K14Q variant data suggests that physical activity and MOTS-c function are interconnected: men with the less-active variant only develop metabolic problems when they are also physically inactive.

Is MOTS-c FDA approved?

No. MOTS-c is not approved by the FDA for any medical use. It is not an approved drug, biological product, or dietary supplement ingredient. It cannot legally be compounded by pharmacies for human use in the United States.

Can athletes use MOTS-c?

No. MOTS-c is prohibited at all times by the World Anti-Doping Agency under Section 4.4.1 (AMPK activators). It was explicitly named on the 2024 prohibited list. There is no Therapeutic Use Exemption pathway available because MOTS-c has no approved medical use.

How is MOTS-c different from SS-31 (Elamipretide)?

Both target mitochondrial function, but through completely different mechanisms. SS-31 is a synthetic peptide that concentrates in the inner mitochondrial membrane, where it stabilizes cardiolipin and directly improves electron transport chain efficiency. MOTS-c is encoded by mitochondrial DNA and works primarily through AMPK activation and nuclear gene regulation. SS-31 has advanced further in human clinical trials (Phase 2/3 for mitochondrial myopathy and heart failure), while MOTS-c remains at the preclinical stage.

Does MOTS-c decline with age?

Yes. Circulating MOTS-c levels drop with age in both mice and humans. In mice, MOTS-c declines in skeletal muscle and blood, coinciding with age-related insulin resistance. In humans, plasma MOTS-c in young adults is roughly 11–21% higher than in middle-aged and older adults. Whether this decline is a cause of aging-related metabolic changes or simply a marker of them is not yet established.

The Bottom Line

MOTS-c represents a genuine scientific breakthrough — the discovery that mitochondria actively produce signaling peptides that regulate metabolism, stress responses, and aging across the entire organism. The preclinical evidence is strong: in mice, MOTS-c prevents obesity, reverses insulin resistance, doubles running capacity in old animals, and activates protective gene programs in the nucleus. In humans, it rises naturally with exercise and declines with age, suggesting a physiological role in metabolic fitness.

But strong preclinical evidence is not the same as a proven therapy. No human trial of MOTS-c has been completed. The only analog to reach human testing (CB4211) was discontinued. Long-term safety is unstudied. Cancer effects are ambiguous. And the FDA has not approved it for anything.

For now, MOTS-c belongs firmly in the category of "promising research compound." The science is real and worth following — particularly as new trials begin to evaluate MOTS-c and its analogs in human populations. But anyone considering using it should understand that they would be experimenting with a substance that has no established safe dose, no proven efficacy in humans, and no regulatory approval anywhere in the world.

The most evidence-backed way to raise your MOTS-c levels today is the one that requires no injection at all: exercise. The Reynolds et al. 2021 study showed that physical activity increases endogenous MOTS-c production in both muscle and blood — a reminder that sometimes the most effective "peptide therapy" is a pair of running shoes.

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