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MOTS-c Peptide Therapy: Another Way to Support Insulin Sensitivity?

Let's begin by revisiting the powerhouse of the cell: the mitochondria.

Glucose undergoes glycolysis in the cytosol, outside the mitochondria, and converts to acetyl coenzyme A (acetyl-CoA). This acetyl-CoA then enters the TCA cycle, also known as the Krebs cycle, which unfolds within the mitochondria. Subsequently, oxidative phosphorylation occurs, generating ATP through the electron transport chain located in the mitochondrial membrane. This highlights the pivotal role of mitochondria in energy metabolism, especially when oxygen is present.

This significance is underscored by the inclusion of mitochondrial dysfunction as one of the nine hallmarks of cellular aging. While other hallmarks were discussed in a prior podcast episode (Episode 31), today's focus remains on mitochondria. Two crucial processes, mitophagy and biogenesis, govern mitochondrial health. Mitophagy involves recycling damaged mitochondria, while biogenesis generates fresh, healthy mitochondria. Both processes must work harmoniously for correct mitochondrial function. Imbalances between proliferation and degradation processes can contribute to various pathological conditions, such as neurodegenerative diseases and age-related disorders.

Today, we're exploring how to support mitochondrial health through a peptide called MOTS-c. Mitochondria possess their own genetic material, distinct from the cell nucleus. Among the proteins encoded by mitochondrial DNA, one stands out: MOTS-c. Mitochondrial DNA undergoes transcription to RNA and translation to proteins, akin to nuclear DNA.

Recent discoveries in mitochondrial-derived peptides (MDPs) include Humanin (HN), small Humanin-like peptides (SHLPs), and mitochondrial open Reading frame of the twelve S-c (MOTS-c). Researchers began investigating MOTS-c in 2015, marking its relative novelty. MOTS-c is encoded within the mitochondrial genome and can translocate from the mitochondria to the cell nucleus under specific conditions, exercise being one of them. This unique localization sets MOTS-c apart from other MDPs.

Before delving into the consequences of MOTS-c's translocation, remember that MOTS-c's expression is age-dependent and abundant in skeletal muscle cells. Remarkably, it's even found in the bloodstream, leading to its designation as a mitochondrial hormone or mitokine. Young individuals exhibit higher blood MOTS-c levels compared to middle-aged and elderly individuals.

With these insights, let's shift our focus to the outcomes of MOTS-c's translocation. One significant result is the activation of the AMPK pathway. AMPK, a critical energy sensor, restores cellular energy balance when ATP levels are low and AMP/ADP levels are high. When MOTS-c activates AMPK, we observe enhanced fatty acid oxidation (fat burning) and glycolysis (sugar breakdown) to generate cellular energy, or ATP. This stems partly from AMPK's ability to phosphorylate acetyl coenzyme A carboxylase (ACC), inactivating it and promoting fuel burning over storage.

Consequently, MOTS-c's actions can be summarized: it activates AMPK, resulting in increased fuel burning (rather than fuel storage due to the ACC enzyme) and, thus increases ATP production. This resonates particularly in scenarios like insulin resistance, where studies indicate MOTS-c's potential to enhance insulin sensitivity and combat diabetes. The reduction in glucose and insulin levels observed in mice injected with MOTS-c following a high-fat diet underlines its promising therapeutic effects.

Shifting to mitochondrial biogenesis, remember the importance of maintaining the balance between mitophagy and biogenesis. As MOTS-c translocates to the nucleus, it triggers AMPK activation, simultaneously boosting the transcription of PGC1-alpha. PGC1-alpha is pivotal for generating new, efficient mitochondria and promoting the removal of damaged ones.

MOTS-c also impacts aging and age-related concerns by increasing NAD+ levels. By increasing NAD+ levels through AMPK activation, sirtuin activity increases. Sirtuins are known for their longevity-enhancing effects. Additionally, MOTS-c's potential in preventing skin aging by increasing dermal collagen underscores its broader benefits.

Transitioning to practical applications, peptide therapy enters the conversation. MOTS-c, a peptide, can be administered via subcutaneous injections under licensed medical guidance. Although some clinics offer oral capsules, injection-based research predominates. This reinforces the importance of consulting a licensed physician for appropriate administration.

Moreover, beyond therapy, we explore how exercise amplifies MOTS-c activity. Human studies reveal that exercise elevates MOTS-c levels in skeletal muscle and circulation. Combining exercise with MOTS-c peptide therapy could potentially offer a powerful synergy, as supported by scientific literature.

In essence, this comprehensive exploration uncovers MOTS-c's multifaceted impacts on cellular health, energy metabolism, insulin resistance, muscle homeostasis, and aging. As we navigate this intricate biochemical landscape, the potential of MOTS-c and its implications for well-being continue to unfold.


Mohtashami, Z., Singh, M. K., Salimiaghdam, N., Ozgul, M., & Kenney, M. C. (2022). MOTS-c, the Most Recent Mitochondrial Derived Peptide in Human Aging and Age-Related Diseases. International journal of molecular sciences, 23(19), 11991.

Palikaras, K., Lionaki, E. & Tavernarakis, N. Balancing mitochondrial biogenesis and mitophagy to maintain energy metabolism homeostasis. Cell Death Differ22, 1399–1401 (2015).

Reynolds JC, Lai RW, Woodhead JST, Joly JH, Mitchell CJ, Cameron-Smith D, Lu R, Cohen P, Graham NA, Benayoun BA, Merry TL, Lee C. MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis. Nat Commun. 2021 Jan 20;12(1):470. doi: 10.1038/s41467-020-20790-0. PMID: 33473109; PMCID: PMC7817689.

Zheng, Y., Wei, Z., & Wang, T. (2023). MOTS-c: A promising mitochondrial-derived peptide for therapeutic exploitation. Frontiers in endocrinology, 14, 1120533.

Hardie D. G. (2011). AMP-activated protein kinase: an energy sensor that regulates all aspects of cell function. Genes & development, 25(18), 1895–1908.

Wan, W., Zhang, L., Lin, Y., Rao, X., Wang, X., Hua, F., & Ying, J. (2023). Mitochondria-derived peptide MOTS-c: effects and mechanisms related to stress, metabolism and aging. Journal of translational medicine, 21(1), 36.

Gao Y, Wei X, Wei P, Lu H, Zhong L, Tan J, Liu H, Liu Z. MOTS-c Functionally Prevents Metabolic Disorders. Metabolites. 2023; 13(1):125.

1 Comment

Wow!! I’m going to have to read that again but that would really help prevent aging issues!

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