MOTS-c

What it is

MOTS-c (mitochondrial open reading frame of the twelve S rRNA type-c) is a 16-amino-acid peptide encoded within the mitochondrial DNA — specifically within the 12S ribosomal RNA gene. It is one of the family of “mitochondrial-derived peptides” (MDPs) discovered over the past decade.

MOTS-c was first characterized in 2015 by Pinchas Cohen’s laboratory at USC. The discovery added to a growing recognition that mitochondria produce signaling peptides. Other mitochondrial-derived peptides include humanin and the SHLP family of peptides.

MOTS-c is not FDA-approved for any use in the United States. Human research is limited and at an early stage.

Mechanism of action

Proposed mechanisms come from laboratory and animal research:

• AMPK activation: has been reported to activate AMP-activated protein kinase, a cellular energy sensor, in cell and animal studies.
• Glucose homeostasis: changes in glucose uptake and insulin sensitivity have been reported in animal models.
• Mitochondrial function: effects on mitochondrial biogenesis and function have been reported in laboratory and animal studies.
• Folate metabolism: laboratory evidence suggests effects on the folate-methionine cycle.
• Inflammatory markers: reduced inflammatory cytokine production has been reported in some preclinical models.
• Age-related levels: observational studies report that circulating MOTS-c levels decline with age; the significance of this is unknown.

Research findings

MOTS-c research is mostly preclinical:

Metabolic findings in animals: in rodent studies, MOTS-c was associated with changes in insulin sensitivity and glucose tolerance.

Aging models: in aged mice, MOTS-c administration was associated with changes in metabolic measures.

Diabetic models: reductions in fasting glucose were reported in diabetic animal models.

Mitochondrial dysfunction: protective effects were reported in some animal and cell models of mitochondrial stress.

Human research: small early-phase studies of MOTS-c or related analogs have been published; benefit in people has not been established.

Well-controlled human trials establishing the effectiveness and safety of MOTS-c are lacking.

Side effects and contraindications

Human safety has not been established in well-controlled trials, and long-term effects are unknown. Products sold outside regulated channels (for example, as “research peptides”) may vary in purity, dose, and sterility.

Caution areas:

• Pregnancy and breastfeeding: safety data are lacking
• Cancer: effects on metabolic and mitochondrial pathways raise theoretical concerns that have not been studied
• Blood sugar: possible additive effects with glucose-lowering medications such as metformin are a theoretical concern

What we don’t yet know

MOTS-c has not accumulated a meaningful clinical evidence base. Long-term safety and any effects in people with multi-year exposure are not characterized. How MOTS-c compares with established metabolic therapies has not been studied. Whether MOTS-c has any effect in healthy adults or in people with metabolic disease, beyond what exercise, diet, and sleep provide, is an open question.