MOTS-c

Overview

MOTS-c (mitochondrial open reading frame of the 12S rRNA-c) is a 16-amino-acid peptide that is not encoded in the nuclear genome but in the mitochondrial genome itself. It was first described in 2015 by the group of Pinchas Cohen at the University of Southern California, and belongs to a new class of signalling molecules: the mitochondrial-derived peptides, sometimes called mitokines. A mitokine is a signalling molecule released from mitochondria that exerts effects elsewhere in the cell or in the body.

The discovery of MOTS-c reshaped the view of what mitochondria do. For a long time the mitochondrion was treated as the cell's power plant and little more. MOTS-c shows that the mitochondrial genome also actively encodes signals that talk to the nucleus. That places MOTS-c at a striking intersection of energy metabolism, the stress response and gene regulation.

The biology of MOTS-c is primarily metabolic. The peptide activates AMPK, the cell's central energy sensor, and is therefore involved in glucose handling, insulin sensitivity and fat metabolism. MOTS-c is released during exercise and is studied as a natural exercise-mimicking molecule. Plasma levels fall with age, which explains the interest from the ageing field. That ageing angle, though, follows from the metabolic biology, not the other way round.

The limit of current knowledge is sharp to draw. Almost everything that is known about administering MOTS-c comes from animal and cell models. In humans there is now extensive data, but of a different kind: circulating levels, correlations, and responses to exercise or feeding. No published study has administered exogenous MOTS-c to humans. That distinction runs through this profile.

Mechanism of action

MOTS-c works along a primary metabolic route and a separate route to the nucleus. Both have been established in cell and animal models.

AMPK activation via the folate cycle

• MOTS-c intervenes in the folate-methionine cycle, a series of reactions that supplies building blocks for purine synthesis. Purines are components of DNA and of energy carriers such as ATP.
• By restraining that cycle, the intermediate AICAR accumulates. AICAR is a natural activator of AMPK.
• AMPK (AMP-activated protein kinase) is the cell's central energy sensor. Its activation increases glucose uptake and stimulates fat oxidation.

Direct binding to CK2

• More recent work in skeletal muscle shows that MOTS-c also binds and activates CK2 directly, an enzyme involved in multiple metabolic pathways. CK2 is a casein kinase that phosphorylates proteins.
• This finding refines the original folate-AICAR-AMPK model and points to a more direct intervention point in muscle.

Translocation to the nucleus under stress

• Under metabolic stress, such as glucose deprivation, MOTS-c translocates to the nucleus.
• There it binds stress-responsive transcription factors, including NRF2, and regulates genes carrying an antioxidant-response element.
• In this way a mitochondrial peptide reaches directly into nuclear gene expression, a form of communication from mitochondrion to nucleus.

Research findings

• Mouse administration: prevented age- and diet-induced insulin resistance and obesity (Lee 2015)
• Aged mice: MOTS-c improved running capacity and physical performance (exercise-like adaptations)
• Mouse: reduced myostatin signalling and muscle atrophy via CK2-PTEN-AKT-FOXO1 (Kumagai 2021)
• Rat: protection against lung and heart ischaemia-reperfusion via nuclear translocation (Li 2025)
• Human RCT: plasma MOTS-c rose after 16 weeks of training in breast cancer survivors; MOTS-c is the measured outcome, not administered (Dieli-Conwright 2021)
• Human infusion: circulating MOTS-c rose after intralipid, blunted by insulin (Ramanjaneya 2019)
• Human genetics: K14Q variant associated with muscle fibre composition, performance, and type 2 diabetes risk

Preclinical administration (animal and cell models)

• In mice, MOTS-c administration prevented the insulin resistance that normally develops with ageing and a high-fat diet, and counteracted diet-induced obesity (Lee 2015).
• In aged mice, MOTS-c improved running capacity and physical performance, with adaptations resembling those of exercise.
• In a mouse model, MOTS-c reduced myostatin signalling (a natural brake on muscle growth) and the associated muscle atrophy (Kumagai 2021).
• In rats, MOTS-c protected against ischaemia-reperfusion injury in lung and heart, via the same nuclear translocation route (Li 2025).

Human data: observation, genetics and response

• In a randomised exercise trial in breast cancer survivors, plasma MOTS-c rose after 16 weeks of training. In that study MOTS-c is the measured outcome of the training, not an administered agent (Dieli-Conwright 2021).
• In healthy subjects and in women with polycystic ovary syndrome, circulating MOTS-c rose after an intralipid infusion; insulin blunted that response (Ramanjaneya 2019).
• A naturally occurring variant of MOTS-c (the K14Q variant, common in East Asian populations) is associated with skeletal muscle fibre composition, with physical performance, and with elevated type 2 diabetes risk. This is a genetic association, not an administration.
• In a small study in healthy physically active subjects, higher serum MOTS-c was associated with greater muscle mass and strength, but not with endurance (Domin 2023).
• In children with obesity, serum MOTS-c was decreased and associated with vascular endothelial function (Luo 2023).

Research context

MOTS-c sits at the heart of a young and rapidly growing research field: that of the mitochondrial-derived peptides. The scientific significance is foundational. If the mitochondrial genome encodes signals that direct the nucleus, the old division of labour between nucleus and mitochondrion is too simple. MOTS-c is, alongside humanin, the most-studied example of that two-way communication.

At the same time this profile requires a distinction that popular sources often blur. The striking effects of MOTS-c (protection against insulin resistance, improved exercise capacity, less muscle atrophy) have been shown by administering the peptide to animals or cell cultures. The human data is of a fundamentally different type. It consists of circulating-level measurements, genetic associations, and responses to exercise or feeding. That data is extensive and consistent, and it makes it plausible that MOTS-c also plays a role in human metabolism. But no published study has administered exogenous MOTS-c to humans and measured a structured outcome.

That difference determines the classification. The presence of substantial human research here does not mean that the efficacy of administered MOTS-c in humans has been demonstrated. It means that MOTS-c is measurable, regulable and biologically relevant in humans: a strong observational basis, but not yet interventional evidence.

Open questions

• No human study has administered exogenous MOTS-c; clinical groups could lead the first interventional studies here.
• Bioavailability and tissue distribution of administered MOTS-c in humans are unknown and require pharmacokinetic work.
• The full spectrum of nuclear gene targets driven by MOTS-c has not yet been mapped.
• The relative contribution of the folate-AICAR-AMPK route versus direct CK2 binding remains to be worked out.
• Interactions between MOTS-c and other mitochondrial-derived peptides, such as humanin, call for dedicated study.

Research outlook

MOTS-c remains a central model for understanding communication between mitochondrion and nucleus.

Its role in age-related metabolic decline and in the response to exercise is an active area of research.

The value of circulating MOTS-c as a biomarker for mitochondrial function and metabolic health is being investigated further.

Direct CK2 binding opens a new mechanistic line of work that warrants deeper characterisation.

Scientific interest

Mitochondrially encoded signalling peptide: evidence that the mitochondrial genome directs the nucleus.

AMPK activation via the folate cycle and direct CK2 binding: two complementary metabolic intervention points.

Exercise-mimicking action: MOTS-c as a molecule that partially reproduces the effects of exercise in animal models.

Age-dependent decline in plasma levels: MOTS-c as a candidate biomarker for metabolic and mitochondrial ageing.

Specifications

References

1. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance · Lee C, Zeng J, Drew BG, et al. · Cell Metabolism · 2015
2. The Mitochondrial-Encoded Peptide MOTS-c Translocates to the Nucleus to Regulate Nuclear Gene Expression in Response to Metabolic Stress · Kim KH, Son JM, Benayoun BA, Lee C · Cell Metabolism · 2018
3. Lipids and insulin regulate mitochondrial-derived peptide (MOTS-c) in PCOS and healthy subjects · Ramanjaneya M, Jerobin J, Bettahi I, et al. · Clinical Endocrinology · 2019
4. MOTS-c reduces myostatin and muscle atrophy signaling · Kumagai H, Coelho AR, Wan J, et al. · American Journal of Physiology - Endocrinology and Metabolism · 2021
5. Effect of aerobic and resistance exercise on the mitochondrial peptide MOTS-c in Hispanic and Non-Hispanic White breast cancer survivors · Dieli-Conwright CM, Sami N, Norris MK, et al. · Scientific Reports · 2021
6. The MOTS-c K14Q polymorphism in the mtDNA is associated with muscle fiber composition and muscular performance · Kumagai H, Natsume T, Kim SJ, et al. · Biochimica et Biophysica Acta - General Subjects · 2021
7. Serum MOTS-C Levels are Decreased in Obese Children and Associated with Vascular Endothelial Function · Luo YH, Xie L, Li JY, et al. · Diabetes, Metabolic Syndrome and Obesity · 2023
8. Mitochondria-derived peptide MOTS-c: effects and mechanisms related to stress, metabolism and aging · Wan W, Zhang L, Lin Y, et al. · Journal of Translational Medicine · 2023
9. Role of MOTS-c in the regulation of bone metabolism · Yi X, Hu G, Yang Y, et al. · Frontiers in Physiology · 2023
10. MOTS-c Serum Concentration Positively Correlates with Lower-Body Muscle Strength and Is Not Related to Maximal Oxygen Uptake — A Preliminary Study · Domin R, Pytka M, Żołyński M, et al. · International Journal of Molecular Sciences · 2023
11. Mitochondria-encoded peptide MOTS-c participates in plasma membrane repair by facilitating the translocation of TRIM72 to membrane · Jia H, Zhou LC, Chen YF, et al. · Theranostics · 2024
12. MOTS-c attenuates lung ischemia-reperfusion injury via MYH9-dependent nuclear translocation and transcriptional activation of antioxidant genes · Li X, Zhan F, Qiu G, et al. · Redox Biology · 2025

Availability

In stock · Batch PEP-MOT-2026-01 · HPLC 99.27 % · released 31 Aug 2026

• MOTS-c 10 mg · product page with price and batch CoA