MOTS-C

What is MOTS-c and How Does It Work

MOTS-c is a small peptide composed of 16 amino acids. This relatively compact molecular structure allows it to diffuse relatively easily within cells and interact with multiple intracellular targets. MOTS-c is a mitochondrial-derived peptide (MDP). It is encoded by the mitochondrial genome, synthesized within mitochondria, and released into the cytoplasm to exert its effects. Mitochondria are commonly regarded as the cell’s “powerhouse.” Beyond their role in energy production, they also generate these biologically active peptides.

MOTS-c inhibits the folate cycle at the 5Me-THF level, leading to accumulation of AICAR [5-aminoimidazole-4-carboxamide dinucleotide]. MOTS-c also elevates cellular NAD+ levels, with NAD serving as a nucleotide precursor. As a mitochondrial signal, MOTS-c stimulates cellular glucose uptake while inhibiting respiration. Glucose absorbed in response to MOTS-c is directed toward the synthetic pentose phosphate pathway (PPP), which provides carbon sources for purine synthesis rather than being metabolized via glycolysis. Additionally, MOTS-c elevates levels of the carnitine shuttle, which transports active fatty acids into mitochondria for β-oxidation. This increases β-oxidation intermediates and reduces intracellular levels of essential and non-essential fatty acids, indicating enhanced lipid utilization. Myocytes stably overexpressing MOTS-c also exhibit increased glucose uptake.

Benefits of MOTS-c

Metabolic Regulation

MOTS-c plays a pivotal role in energy metabolism. It modulates insulin sensitivity and promotes glucose uptake. For instance, in insulin-resistant cell models, MOTS-c enhances cellular insulin responsiveness, enabling more efficient glucose uptake and utilization—akin to opening a “gateway” for nutrient acquisition. It also participates in regulating fatty acid oxidation, helping maintain balanced intracellular lipid metabolism.

Cellular Stress Responses

When cells encounter stressors such as oxidative stress or nutrient deprivation, MOTS-c expression levels undergo changes. It activates intracellular stress signaling pathways, enhancing cellular resilience. For instance, under oxidative stress conditions, MOTS-c induces the expression of antioxidant enzymes, aiding cells in scavenging excess free radicals and mitigating oxidative damage, thereby safeguarding cellular integrity and function.

Aging and Longevity Association

Research indicates MOTS-c is closely linked to the aging process. It modulates cellular senescence phenotypes, delaying cellular aging by improving metabolic efficiency and stress response capabilities. In model organism studies, elevated MOTS-c levels extend lifespan, likely achieved through activation of anti-aging genes and signaling pathways.

MOTS-c Dosage

5-15 mg weekly, divided into 2-3 injections. Administer subcutaneously (abdomen, thigh, or flank area). Beginners typically start with 5 mg weekly, gradually increasing based on response and tolerance. MOTS-c is most effective when used: in the morning on an empty stomach; 30-60 minutes before fasting aerobic exercise or training; and on non-training days to maintain metabolic signaling.

MOTS-c Side Effects

Redness, swelling, or minor bruising at injection site.

Mild fatigue or drowsiness: Especially during initial adaptation to mitochondrial AMPK activation.

Some users report suppressed appetite, while others experience increased hunger due to enhanced fat mobilization.

Muscle cramps: Rare, potentially linked to increased fatty acid metabolism and electrolyte shifts.

Hypoglycemia: Extremely rare, but theoretically possible when combined with fasting, clean carbohydrates, or insulin sensitizers.

Thyroid or cortisol rhythm disruption: Occurs only with extremely high or prolonged use.