Peptides for Mitochondrial Health – Mots-c, Epitalon, SS-31, FOX-04, 5-Amino-1MQ

As we have spoken about in posts such as Cipro Toxicity, mitochondria is the part of the cell that is responsible for producing energy in the form of adenosine triphosphate (ATP). While it’s main function is to carry out cellular respiration, a process that converts nutrients from food into ATP, there are many other functions mitochondria perform, including metabolic signaling, calcium regulation, autophagy (cellular clean-up) and apoptosis (cell death), neurogenesis (growth of new nerve tissue) and neuronal plasticity (aka neuroplasticity- our brain’s ability to grow and adapt), as well as the synthesis of other molecules (especially those in the immune system). Mitochondria are so much more than just the powerhouse of the cell! Our health is directly related to the health of our mitochondria, so it’s imperative that they function optimally. Reasons why mitochondria might be impaired or damaged include:

• Aging
• Inadequate diet
• Poor sleep
• Lack of exercise
• Genetics
• Heavy and toxic metals
• Pollutants
• Free radicals
• Prescription drugs
• Alcohol

There are many condition that are caused or made worse by mitochondrial dysfunction, such as the following per Pizzorno (2014):

• Early aging
• Amyotrophic lateral sclerosis
• Alzheimer’s disease
• Autism
• Cardiovascular disease
• Chronic fatigue syndrome
• Dementia
• Diabetes
• Huntington’s disease
• Migraine headache
• Parkinson’s disease

A great way to directly influence the health of our mitochondria is through the use of peptides. They can promote mitochondrial biogenesis (increasing the number and function of mitochondria within cells), increase antioxidant activity, stabilize mitochondrial membranes, assist with ATP production, and modulate cell signaling and protection. Some of the best peptides for this are MOTS-c, Epitalon, SS-31, FOX04, 5-Amino-1MQ.

MOTS-c

Mitochondrial Open Reading Frame of the Twelve-C, also known as MOTS-c, is a small peptide and one of the more recently studied. It is “produced by a mitochondrial gene, and it has been shown to play a key role in signaling and energy production…restores homeostasis by initiating catabolic process for ATP production… decreases insulin resistance…[and] increases athletic performance” (Seeds, 2020). MOTS-c plays a role in mitochondrial biogenesis (new cell growth) which enhances cellular energy production and overall mitochondrial function. It influences energy metabolism by improving glucose homeostasis and insulin sensitivity and enhances glucose uptake and utilization in cells which leads to improved energy metabolism.  Additionally, it reduces oxidative stress within mitochondria by scavenging reactive oxygen species (ROS) which preserves mitochondrial integrity by preventing oxidative damage to mitochondria, as well as contributes to mitochondrial health and efficiency. It can also help prevent cell apoptosis which helps maintain cell viability and contribute to overall mitochondrial function. In clinical studies, it has been shown to have beneficial effects on skin aging, muscular homeostasis, diabetes, Alzheimer disease, cardiovascular disease, and osteoporosis.  (Mohtashami et al., 2022)

Epitalon

Also known as Epithalon or Epithalone, this peptide has many uses including increasing emotional resilience, acting as an antioxidant, helping to regulate the endocrine system and assisting with cellular repair (Seeds, 2020). In regards to its effect on mitochondria, clinical studies have shown that it can stimulate mitochondrial biogenesis, leading to an increase in the number and function of mitochondria within cells (Yue et al., 2022). By promoting mitochondrial biogenesis, Epitalon enhances cellular energy production and overall metabolism. Epitalon has also shown to increase oxidative stress protection through its antioxidant properties. It also helps to lengthen telomeres, which slows down the aging process and contributes to improved mitochondrial function (Khavinson et al., 2003). Lastly, it has been shown to inhibit cellular senescence which impacts mitochondrial function (Khavinson et al., 2003)

SS-31

The Szeto-Schiller peptide, SS-31, is a mitochondria-targeted antioxidant and membrane stabilizer that “protects and restores mitochondrial structure, promotes ATP synthesis, reduces electron leakage and cardiolipin peroxidation, and has no effect on healthy mitochondria” (Zhu, 2022). It does this by scavenging reactive oxygen species (ROS), which helps protect mitochondrial components such as proteins, lipids, and DNA from oxidative damage, thereby preserving mitochondrial function. By stabilizing the mitochondrial inner membrane, it assists with electron transport and ATP production and energy metabolism. SS-31 has anti-apoptotic properties, meaning it can inhibit programmed cell death. It helps maintain mitochondrial membrane potential and prevent the release of pro-apoptotic factors from mitochondria, thereby preserving cell viability (Pang, 2015). Additionally, SS-31 has been shown to reverse the mitochondria fragmentation (Machiraju et al., 2019). This helps with both normal mitochondria degradation as well as mitochondrial dysfunction-related conditions such as heart failure, ischemia-reperfusion injury, neurodegenerative diseases, and metabolic disorders.

FOX04

The curiously named Forkhead box O4, FOX04, is a protein that is involved in regulating various cellular processes, including cell cycle arrest, apoptosis, DNA repair, stress response, metabolism, and longevity (Huang, 2021).  While FOXO4 can influence mitochondrial function indirectly through its regulatory effects on cellular processes, it does not directly target mitochondria like the other mitochondria-targeted peptides listed above. This protein has an effect on cellular senescence and apoptosis, and it interacts with other proteins and signaling pathways to regulate gene expression, affecting cellular responses to stress, DNA repair, and cell survival. Although FOXO4’s specific effects on mitochondria are as direct as the other peptides above, it is known to regulate the expression of genes involved in oxidative stress response and energy metabolism, which can impact mitochondrial function indirectly (Liu, 2019).

5-Amino-1MQ

This peptide is one of the newer ones, but has shown great clinical efficacy in blocking the NNMT enzyme (nicotinamide N-methyltransferase), which makes our metabolic cycle sluggish. It does this without affecting any other enzyme or part of the metabolic cycle (Neelakantan, 2018). While other peptides inhibit the function of the NNMT enzyme, studies have shown that 5-Amino-1MQ is the most effective. The mechanism of action is that it affects the production of NAD+ on an intracellular level (Neelakantan, 2019). Besides mitochondrial health, it is also being studied as an effective therapy for weight loss.

References

Cheng, J., Nanayakkara, G., Shao, Y., Cueto, R., Wang, L., Yang, W. Y., Tian, Y., Wang, H., & Yang, X. (2017). Mitochondrial Proton Leak Plays a Critical Role in Pathogenesis of Cardiovascular Diseases. Advances in experimental medicine and biology, 982, 359–370. https://doi.org/10.1007/978-3-319-55330-6_20

Huang, Y., He, Y., Makarcyzk, M. J., & Lin, H. (2021). Senolytic peptide FOXO4-dri selectively removes senescent cells from in vitro expanded human chondrocytes. Frontiers in Bioengineering and Biotechnology, 9. https://doi.org/10.3389/fbioe.2021.677576

Khavinson, V. K.h, Bondarev, I. E., & Butyugov, A. A. (2003). Epithalon peptide induces telomerase activity and telomere elongation in human somatic cells. Bulletin of experimental biology and medicine, 135(6), 590–592. https://doi.org/10.1023/a:1025493705728

Kim, S. J., Miller, B., Mehta, H. H., Xiao, J., Wan, J., Arpawong, T. E., Yen, K., & Cohen, P. (2019). The mitochondrial-derived peptide MOTS-c is a regulator of plasma metabolites and enhances insulin sensitivity. Physiological reports, 7(13), e14171. https://doi.org/10.14814/phy2.14171

Liu, H., Wang, L., Weng, X., Chen, H., Du, Y., Diao, C., Chen, Z., & Liu, X. (2019). Inhibition of Brd4 alleviates renal ischemia/reperfusion injury-induced apoptosis and endoplasmic reticulum stress by blocking FoxO4-mediated oxidative stress. Redox biology, 24, 101195. https://doi.org/10.1016/j.redox.2019.101195

Lobo, V., Patil, A., Phatak, A., & Chandra, N. (2010). Free radicals, antioxidants and functional foods: Impact on human health. Pharmacognosy reviews, 4(8), 118–126. https://doi.org/10.4103/0973-7847.70902

Machiraju, P., Wang, X., Sabouny, R., Huang, J., Zhao, T., Iqbal, F., King, M., Prasher, D., Lodha, A., Jimenez-Tellez, N., Ravandi, A., Argiropoulos, B., Sinasac, D., Khan, A., Shutt, T. E., & Greenway, S. C. (2019). SS-31 peptide reverses the mitochondrial fragmentation present in fibroblasts from patients with DCMA, a mitochondrial cardiomyopathy. Frontiers in Cardiovascular Medicine, 6. https://doi.org/10.3389/fcvm.2019.00167 

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. https://doi.org/10.3390/ijms231911991

Neelakantan, H., Vance, V., Wetzel, M. D., Wang, H. L., McHardy, S. F., Finnerty, C. C., Hommel, J. D., & Watowich, S. J. (2018). Selective and membrane-permeable small molecule inhibitors of nicotinamide N-methyltransferase reverse high fat diet-induced obesity in mice. Biochemical pharmacology, 147, 141–152. https://doi.org/10.1016/j.bcp.2017.11.007

Neelakantan, H., Brightwell, C. R., Graber, T. G., Maroto, R., Wang, H. L., McHardy, S. F., Papaconstantinou, J., Fry, C. S., & Watowich, S. J. (2019). Small molecule nicotinamide N-methyltransferase inhibitor activates senescent muscle stem cells and improves regenerative capacity of aged skeletal muscle. Biochemical pharmacology, 163, 481–492. https://doi.org/10.1016/j.bcp.2019.02.008

Nunnari, J., & Suomalainen, A. (2012). Mitochondria: in sickness and in health. Cell, 148(6), 1145–1159. https://doi.org/10.1016/j.cell.2012.02.035

Pang, Y., Wang, C., & Yu, L. (2015). Mitochondria-Targeted Antioxidant SS-31 is a Potential Novel Ophthalmic Medication for Neuroprotection in Glaucoma. Medical hypothesis, discovery & innovation ophthalmology journal, 4(3), 120–126.

Pizzorno J. (2014). Mitochondria-Fundamental to Life and Health. Integrative medicine (Encinitas, Calif.), 13(2), 8–15.

Seeds, W. A. (2020). The peptide protocols: A handbook for practitioners. Spire Institute.

Yue, X., Liu, S. L., Guo, J. N., Meng, T. G., Zhang, X. R., Li, H. X., Song, C. Y., Wang, Z. B., Schatten, H., Sun, Q. Y., & Guo, X. P. (2022). Epitalon protects against post-ovulatory aging-related damage of mouse oocytes in vitro. Aging, 14(7), 3191–3202. https://doi.org/10.18632/aging.204007

Zhu, Y., Luo, M., Bai, X., Li, J., Nie, P., Li, B., & Luo, P. (2022). SS-31, a Mitochondria-Targeting Peptide, Ameliorates Kidney Disease. Oxidative medicine and cellular longevity, 2022, 1295509. https://doi.org/10.1155/2022/1295509

About the author: Mary Genevieve Carty, MS, MHEd holds Masters degrees in Complementary and Integrative Health as well as Higher Education and is currently a doctoral student in Health Science at George Washington University’s College of Medicine and Health Science.  She is passionate about holistic health and wellness, and has additional training in teaching, Reiki, and Tapping/ Emotional Freedom Technique. Her research interests include resiliency, psychoneuroimmunology, neuroplastic pain, placebo/ nocebo effect, and bioenergy therapies.  The views she expresses are her own, and do not reflect any affiliation.