MOTS-c: Functions and Benefits

MOTS-c is a mitochondrial-derived peptide composed of 16 amino acids, encoded by the 12S rRNA region of the mitochondrial genome. Under resting conditions, MOTS-c resides in the mitochondria; however, during metabolic stress, it translocates to the nucleus to regulate nuclear gene expression and promote cellular homeostasis. This peptide is detectable in various tissues and plasma, though its levels decline with age [1].

Functions

The core function of MOTS-c is the regulation of metabolic homeostasis, specifically:

(1) Improving glucose metabolism: MOTS-c targets skeletal muscle to enhance glucose uptake and utilization, promoting glucose entry into cells for glycolysis via activation of the AMPK pathway. Animal studies demonstrate that acute systemic administration of MOTS-c significantly lowers non-fasting blood glucose levels and improves glucose tolerance [2].

(2) Regulating lipid metabolism: MOTS-c enhances fatty acid β-oxidation and reduces visceral fat and hepatic steatosis while increasing thermogenesis, suggesting it may promote the thermogenic activity of brown/beige adipose tissue.

(3) Acting as an exercise mimetic: Research indicates that exercise significantly upregulates MOTS-c levels in skeletal muscle and plasma. MOTS-c may function as an exercise-induced signaling molecule that mimics the metabolic benefits of exercise, holding promise for development as an "exercise mimetic" to help individuals with limited mobility improve their metabolic health.

(4) Regulating nuclear gene expression: During metabolic stress, MOTS-c translocates to the nucleus in an AMPK-dependent manner and binds to ARE-regulated transcription factors, thereby enhancing cellular stress resistance.

Benefits

Due to its significant physiological functions, MOTS-c offers a wide range of health benefits, including:

(1) Combating insulin resistance and type 2 diabetes: MOTS-c can reverse age-related insulin resistance in skeletal muscle. Systemic administration of MOTS-c to aged mice restores their insulin sensitivity to levels comparable to those of young mice. In models of high-fat diet-induced obesity and insulin resistance, MOTS-c prevents these conditions and mitigates visceral fat accumulation and hepatic steatosis caused by the diet.

(2) Delaying the aging process: MOTS-c levels decline with age, and restoring these levels ameliorates age-related metabolic dysfunction. MOTS-c exerts potential life-extending effects—linked to known longevity-regulating mechanisms such as methionine restriction—by increasing intracellular NAD⁺ levels, activating the SIRT1 pathway, and restricting the folate/methionine cycle.

(3) Cardiovascular protection: Studies indicate that MOTS-c protects against cardiac dysfunction and pathological remodeling; it prevents the progression of heart failure by activating the AMPK pathway and may improve cardiac function in patients with diabetes and heart failure via the NRG1-ErbB4 pathway.

(4) Anti-inflammatory and analgesic effects: MOTS-c reduces pro-inflammatory cytokine levels while increasing anti-inflammatory cytokines; it produces analgesic and anti-inflammatory effects by activating the AMPK pathway and inhibiting the MAP kinase/c-Fos pathway.

(5) Promoting exercise adaptation: MOTS-c activates AMPK in skeletal muscle and increases the expression of the downstream glucose transporter GLUT4; acting as a mitochondrial signal, it may mediate the exercise-induced mitochondrial hormetic response, thereby enhancing exercise tolerance and physiological adaptability [2].

References

[1] Zheng, Y., Wei, Z., Wang, T. (2023). MOTS-c: A promising mitochondrial-derived peptide for therapeutic exploitation. Frontiers in Endocrinology, 14, 1120533. https://doi.org/10.3389/fendo.2023.1120533

[2] Lee, C., Kim, K. H., Cohen, P. (2016). MOTS-c: A novel mitochondrial-derived peptide regulating muscle and fat metabolism. Free Radical Biology and Medicine, 100, Pages 182-187. https://doi.org/10.1016/j.freeradbiomed.2016.05.015

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