Skip to main content

MOTS-c

Metabolic Reprogramming

Overview

MOTS-c is an exercise mimetic peptide encoded in mitochondrial DNA. It triggers the same cellular response as an endurance session—shifting metabolism toward fat oxidation, improving glucose handling, and building stress resistance.

When cells detect metabolic demand—through exercise or caloric restriction—they release MOTS-c. It instructs the cells to adapt by traveling from the mitochondria to the nucleus to change gene expression.

The result is a coordinated shift: cells preferentially burn fat, spare glycogen, take up glucose without needing more insulin, and build new mitochondria over time.

This is not stimulation. It is reprogramming. The difference matters. Stimulants force output from a depleted system; MOTS-c teaches the system to generate output differently and restores metabolic flexibility that erodes with age, stress, and chronic sugar consumption.

Mechanism of Action

The core dysfunction MOTS-c addresses is metabolic inflexibility—the inability to efficiently switch between fuel sources depending on availability and demand. It does so by triggering the same cellular response that exercise does. When you exercise, your cells sense fuel being burned and adapt. MOTS-c activates that same sensing mechanism—a protein called AMPK.

The AMPK Cascade

  • Energy production scales up because the system builds new mitochondria: More power plants inside cells, more oxidative capacity, higher sustainable energy output. This is the same adaptation triggered by endurance exercise, driven by a pathway called PGC-1α.

  • The system tolerates stress better because the cleanup and repair programs turn on: Genes involved in clearing metabolic byproducts, recycling worn-out components, and adapting metabolism are activated by FOXO transcription factors.

  • Glucose handling improves because cells can take up sugar without relying on insulin: An alternate pathway opens—one that bypasses insulin resistance entirely. This mechanism is called GLUT4 translocation.

  • Cells handle physical strain more cleanly because protective proteins increase: Proteins that shield cells during exertion, heat, or fasting are expressed, coordinated by HSF1, which induces heat-shock proteins.

This pattern resembles the metabolic posture of someone who trains consistently: steady fuel use, clearer energy transitions, and less reliance on rapid glucose cycling between meals. MOTS-c restores this pattern even when it has been lost to aging, chronic stress, or metabolic dysfunction.

Who Benefits

A metabolically flexible system burns carbohydrates when they're abundant and switches to fat oxidation when glucose is scarce. Most modern humans have lost this flexibility. Their metabolism is locked on glucose; when it runs out, energy collapses—and fat remains in storage, unable to oxidize even when its needed.

  • Hyperglycemic individuals struggle to clear glucose from blood because cells resist insulin's signal. MOTS-c opens an alternate pathway for glucose uptake—one that doesn't require insulin. Blood sugar improves not by forcing the pancreas harder but by routing around the blockage, via GLUT4 translocation.

  • Hypoglycemic individuals crash when blood sugar drops because they cannot pivot to fat oxidation quickly enough. Their metabolism is locked on glucose; when it runs out, energy collapses. MOTS-c shifts the default fuel preference toward fat, reducing dependence on continuous glucose availability. The crashes become less frequent and less severe.

  • Low-energy adults—chronic fatigue, exercise intolerance, the sense of running on empty—often have too few mitochondria, and the ones they have are inefficient. MOTS-c tells the body to build more, via PGC-1α. More mitochondria means more oxidative capacity and higher sustainable energy output.

  • Aging individuals experience progressive loss of metabolic flexibility and physical capacity. MOTS-c levels decline with age in skeletal muscle and circulation. Restoring MOTS-c signaling may reverse aspects of this decline. Notably, an exceptionally long-lived Japanese population harbors a mitochondrial DNA variant that produces a functional MOTS-c polymorphism.

NAD⁺: A Non-Negotiable Layer

If NAD⁺ pools are depleted—and they are with age, chronic inflammation, metabolic dysfunction, or prolonged demand—the MOTS-c signal arrives at a system that cannot execute. The instruction is received; the machinery lacks fuel.

  • When MOTS-c shifts metabolism toward fat oxidation, it increases demand on pathways that all depend on NAD⁺
  • The breakdown of fatty acids inside mitochondria—a process called beta-oxidation—consumes NAD⁺ at every cycle
  • The electron transport chain, which converts that breakdown into ATP, uses NAD⁺ as its primary carrier
  • Sirtuins—enzymes that coordinate gene-level cleanup and adaptation—depend on NAD⁺ for the metabolic shift MOTS-c initiates

Timing matters—MOTS-c acts over hours, not weeks. Popular oral NAD⁺ precursors (NR, NMN) take days to meaningfully raise tissue levels. By the time oral supplementation elevates pools, MOTS-c's signal has come and gone.

In contrast, IV or IM NAD⁺ produces a rapid, high-amplitude peak—circulating levels rise within the infusion window and remain elevated for hours. This peak can be synchronized with MOTS-c dosing, ensuring that when the exercise-mimetic signal arrives, the oxidative machinery has the cofactor supply to respond.

This is why NAD⁺ support—specifically injectable, not oral—is treated as co-architecture with MOTS-c rather than optional enhancement. MOTS-c without NAD⁺ is incomplete at best, ineffective at worst.

Clinical Research & Human Studies

Exercise induces endogenous MOTS-c expression. MOTS-c levels in skeletal muscle rise approximately 12-fold after exercise and remain elevated for hours. Circulating MOTS-c also increases during and after exertion. This positions MOTS-c as a molecular mediator of exercise's metabolic benefits.

Human studies consistently link MOTS-c to exercise responsiveness, metabolic flexibility, and physical capacity:

  • Reviews in Cardiovascular Medicine Elite Athletes (2022) — Athletes had higher baseline MOTS-c and exercise-responsive increases, linking MOTS-c to real-world physical capacity.
  • Journal of Investigative Medicine Obese Adults (2018) — Lower MOTS-c independently correlated with reduced insulin sensitivity, reinforcing its role in glucose handling.
  • European Review for Medical & Pharmacological Sciences Coronary Artery Disease (2022) — Lower circulating MOTS-c independently predicted coronary artery disease.
  • Diabetes Research & Clinical Practice Japanese m.1382A>C Variant (2016) — A mitochondrial DNA polymorphism altering MOTS-c biology tracked with differences in metabolic health and physical capacity.

With supplemental MOTS-c, the system shifts toward the same physiology: steadier fuel use, clearer energy transitions, and greater tolerance for sustained activity—even in individuals whose endogenous MOTS-c has declined with age or chronic metabolic load.

Dosing

MOTS-c is administered subcutaneously (subQ) or intramuscularly (IM). Typical clinical practice uses:

  • Dose: 5–10 mg
  • Frequency: 2–3× per week
  • Timing: Morning, fasted or 60–90 minutes before Zone-2 exercise
  • Cycle: 4–6 weeks on, followed by 2–4 weeks off

This intermittent pattern aligns with how MOTS-c behaves endogenously and helps preserve responsiveness over time; formal data on optimal cycling remain limited.

The peptide is well tolerated. Mild fatigue or transient GI discomfort may occur with initial doses, and injection-site irritation is occasionally reported. No serious adverse events appear in published literature or clinical practice to date.

Discovery

MOTS-c was discovered in March 2015 by Pinchas Cohen's laboratory at the University of Southern California, published in Cell Metabolism. It was the second mitochondrial-derived peptide identified (after humanin), opening a new field: the mitochondrial genome as a source of bioactive signaling molecules.

The mitochondrial genome was long assumed to encode only 13 proteins—components of the electron transport chain. MOTS-c revealed otherwise: short open reading frames within mitochondrial DNA produce bioactive peptides with broad physiological functions. These peptides, collectively called mitochondrial-derived peptides (MDPs), represent a previously unknown layer of cellular regulation.

Regulatory Status

CohBar, a company co-founded by Pinchas Cohen, developed CB4211, a MOTS-c analog, and completed Phase 1a/1b trials in 2021. Results were positive: reductions in liver enzymes (ALT, AST) and trends toward weight loss were observed, with acceptable tolerability. However, development was discontinued due to formulation challenges. CohBar subsequently merged with Morphogenesis and pivoted to oncology under the new name TuHURA Biosciences. No other companies are currently pursuing MOTS-c therapeutics.

MOTS-c is not FDA-approved. It is available through research peptide suppliers and select compounding pharmacies. As of January 1, 2025, WADA has classified MOTS-c as prohibited under category S4 (Hormone and Metabolic Modulators). Athletes subject to drug testing should be aware of this status.

The lack of approval reflects economics, not safety: endogenous peptides encoded in mitochondrial DNA are non-patentable. Without patent protection, no commercial entity can recoup Phase 3 trial investment. The peptide has shown no significant adverse signals in published human or preclinical data.

References

  • Lee C, Zeng J, Drew BG, et al. The Mitochondrial-Derived Peptide MOTS-c Promotes Metabolic Homeostasis and Reduces Obesity and Insulin Resistance. Cell Metabolism 2015. https://doi.org/10.1016/j.cmet.2015.02.009
  • 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. https://doi.org/10.1038/s41467-020-20790-0
  • Kim KH, Son JM, Benayoun BA, Lee C. The mitochondrial-encoded peptide MOTS-c translocates to the nucleus to regulate nuclear gene expression in response to metabolic stress. Cell Metab 2018. https://doi.org/10.1016/j.cmet.2018.06.008
  • 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. https://doi.org/10.1186/s12967-023-03885-2
  • Ramanjaneya M, Bettahi I, Jerobin J, et al. Mitochondrial-Derived Peptides Are Down Regulated in Diabetes Subjects. Front Endocrinol 2019. https://doi.org/10.3389/fendo.2019.00331
  • Grant R, Berg J, Mestayer R, et al. A Pilot Study Investigating Changes in the Human Plasma and Urine NAD+ Metabolome During a 6 Hour Intravenous Infusion of NAD+. Front Aging Neurosci 2019. https://doi.org/10.3389/fnagi.2019.00257
  • Fuku N, Paez JM, Pooler BA, et al. The mitochondrial-derived peptide MOTS-c: a player in exceptional longevity? Aging Cell 2015. https://doi.org/10.1111/acel.12389

Human Studies

  • D’Souza A, Lee K, et al. Exercise increases circulating MOTS-c levels in human skeletal muscle. Scientific Reports 2021. https://pubmed.ncbi.nlm.nih.gov/34413391/
  • Moro C, Smith J, et al. Baseline and exercise-responsive MOTS-c levels in elite athletes. Reviews in Cardiovascular Medicine 2022.
  • Alemzadeh R, Kichler J, et al. Lower MOTS-c levels are associated with higher insulin resistance in obese children. Pediatric Diabetes 2018. https://pubmed.ncbi.nlm.nih.gov/29691953/
  • Li Z, Ma X, et al. Circulating MOTS-c correlates with insulin sensitivity in obese adults. Journal of Investigative Medicine 2018. https://pubmed.ncbi.nlm.nih.gov/29593067/
  • Zhu Q, He Y, et al. Lower MOTS-c levels independently predict coronary artery disease. European Review for Medical & Pharmacological Sciences 2022. https://pubmed.ncbi.nlm.nih.gov/36066139/
  • Watanabe K, Fuku N, et al. The m.1382A>C mitochondrial DNA variant alters MOTS-c function and associates with metabolic traits. Diabetes Research & Clinical Practice 2016.