Is MOTS-C (Mitochondrial Open Reading Frame of the 12S rRNA-type C) safe for use in humans?

MOTS-c: Understanding Safety and Therapeutic Potential

MOTS-c is a mitochondrial-derived peptide that shows promising therapeutic potential in preclinical studies, but currently lacks FDA approval and sufficient human safety data to recommend for clinical use.

What is MOTS-c?

• MOTS-c (Mitochondrial Open Reading Frame of the 12S rRNA Type-C) is a 16-amino acid peptide encoded by the mitochondrial genome, specifically the 12S rRNA region 1
• It functions as a mitochondrial-derived signaling molecule that can translocate to the nucleus during metabolic stress to regulate nuclear gene expression 1, 2
• MOTS-c is expressed in various tissues and is also found in plasma, with levels that tend to decrease with age 1

Physiological Functions and Mechanisms

• MOTS-c primarily acts through the Folate-AICAR-AMPK pathway, influencing energy metabolism, insulin sensitivity, and stress responses 2
• It regulates the expression of stress adaptation-related genes with antioxidant response elements (ARE) 2
• In preclinical models, MOTS-c has demonstrated:
  • Improvement of glucose metabolism in skeletal muscle 1
  • Prevention of skeletal muscle atrophy by suppressing lipid infiltration 3
  • Modulation of adipogenesis-related genes within the PPAR pathway 3
  • Reduction of circulating inflammatory cytokines (IL-1β, IL-6, CXCL1, MCP-1) 3

Safety Considerations

• There are no established clinical guidelines regarding the safety of MOTS-c for human use 4
• Unlike FDA-approved medications that undergo rigorous safety testing, MOTS-c has not received FDA approval for any clinical indication 4
• Current research on MOTS-c in humans is limited to observational studies rather than controlled safety trials 5, 6
• The International Society for Stem Cell Research guidelines emphasize the need for comprehensive safety evaluation before using novel biological products in humans 4

Human Research Findings

• In breast cancer survivors, a 16-week exercise intervention increased MOTS-c levels in non-Hispanic White participants but not in Hispanic participants, suggesting ethnic-specific responses 5
• Plasma MOTS-c concentrations appear similar between lean and obese individuals (0.48±0.16 vs 0.52±0.15 ng/mL), but correlate with insulin sensitivity markers only in lean individuals 6
• These findings suggest that MOTS-c regulation may be altered in different metabolic states and ethnic backgrounds 5, 6

Potential Therapeutic Applications

• Preclinical research suggests MOTS-c may have potential applications for:
  • Age-related metabolic decline 1, 2
  • Insulin resistance and diabetes 1, 6
  • Obesity management 1
  • Muscle atrophy prevention 3
  • Cardiovascular disease 1, 2
  • Inflammatory conditions 2, 3

Current Status and Recommendations

• MOTS-c remains an investigational compound without established clinical safety profiles or dosing guidelines 4
• The Trends in Molecular Medicine guidelines emphasize that novel biological products require comprehensive safety evaluation before clinical use 4
• Unlike approved medications that have undergone rigorous clinical trials, MOTS-c lacks the safety data necessary for clinical recommendation 4

Conclusion

• While MOTS-c shows promising therapeutic potential in preclinical studies, there is insufficient human safety data to recommend its use outside of clinical trials 4, 1
• Patients interested in MOTS-c should be advised to wait for properly conducted clinical trials and eventual FDA approval before considering its use 4