MOTS-C

MOTS-C Research Overview

MOTS-c is a 16-amino-acid peptide encoded in mitochondrial DNA that acts as a metabolic signal, improving insulin sensitivity and exercise capacity in mice. It is studied for fat loss, endurance, and metabolic aging.

Also known as: Mitochondrial ORF of the 12S rRNA type-c, Mitochondrial-derived peptide MOTS-c, CB4211 (analog)

Background

MOTS-c was identified in 2015 by Changhan Lee and Pinchas Cohen at the University of Southern California. It is encoded in a short open reading frame inside the mitochondrial 12S ribosomal RNA gene, which was assumed for decades to make only RNA. That makes it one of a small family of mitochondrial-derived peptides, alongside humanin and the SHLPs, and it reframed mitochondria as organelles that send out their own hormone-like signals.

The mouse data are what drive interest. MOTS-c injections prevented diet-induced obesity and insulin resistance, improved glucose handling in aged mice, and, in a 2021 study, restored exercise capacity in old mice to the point where treated animals doubled their running time. Levels in muscle and blood rise with exercise in clinical literature and decline with age. A natural variant of the MOTS-c sequence found in East Asian populations is linked to higher type 2 diabetes risk, which is indirect human evidence that the peptide matters metabolically.

Direct human treatment data are limited. CohBar developed a modified analog, CB4211, which completed a phase 1a/1b study in people with obesity and fatty liver, showing acceptable safety and modest changes in glucose and body weight, before the company changed direction. Native MOTS-c has not been through a proper human trial. The community treats it as an exercise mimetic and metabolic aid, usually injected a few times per week.

Mechanistic Profile

MOTS-c works largely through the folate and methionine cycles. AMPK activation increases glucose uptake in skeletal muscle, boosts fatty acid oxidation, and improves mitochondrial biogenesis, which together resemble the effects of exercise. Under metabolic stress MOTS-c also moves from the cytoplasm into the nucleus, where it binds stress-response transcription factors including NRF2 and adjusts expression of antioxidant and metabolic genes. It acts on muscle preferentially, with smaller effects on liver and fat. Its rise with exercise and decline with age suggest it is a normal part of how mitochondria communicate their energy status to the rest of the body.

Reported Research Findings

• MOTS-c prevented high-fat-diet obesity and insulin resistance in mice and improved insulin sensitivity in aged mice. (rodent)

• MOTS-c treatment roughly doubled running capacity in old mice and improved physical performance in young mice on a high-fat diet. (rodent)

• MOTS-c translocates to the nucleus during metabolic stress and regulates stress-response gene expression. (in vitro)

• Exercise raised MOTS-c levels in human skeletal muscle and plasma. (human pilot)

• The CB4211 analog completed a phase 1 study in obesity and fatty liver with acceptable safety and modest metabolic signals. (human pilot)

• A natural MOTS-c sequence variant in East Asian populations is associated with increased type 2 diabetes risk. (human pilot)

Analytical Validation, Formulation and Storage

• Purity: 99% or higher as verified by HPLC, with a third-party certificate of analysis available per batch.

• Formulation: lyophilised (freeze-dried) powder in a sterile sealed glass vial, to be reconstituted with an appropriate solvent for laboratory use.

• Reported half-life: Not well characterized; likely short, well under an hour, though tissue effects last longer.

• Storage: keep lyophilised material cool, dark and dry (long-term at or below -20 °C). Store reconstituted solutions refrigerated, avoid repeated freeze-thaw cycles and use within laboratory-defined windows.

Selected Literature

• The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metabolism, 2015.

• MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis. Nature Communications, 2021.

• The mitochondrial-encoded peptide MOTS-c translocates to the nucleus to regulate nuclear gene expression in response to metabolic stress. Cell Metabolism, 2018.

• A pro-diabetogenic mtDNA polymorphism in the mitochondrial-derived peptide MOTS-c. Aging, 2021.

Cloud Aminos supplies MOTS-C as a high-purity research material intended strictly for controlled laboratory use in vitro or in established animal models. This compound is not approved as a drug, diagnostic or dietary ingredient and is not manufactured, packaged or marketed for human consumption, self-experimentation, clinical application or any use outside properly designed and ethically approved research protocols.