Mitochondrial-derived peptides (MDPs) activated by physical exercise as therapeutic targets for metabolic disorders: A systematic review

Background: Type 2 diabetes mellitus and metabolic diseases are increasing worldwide and are closely linked to mitochondrial dysfunction. Mitochondrial-derived peptides (MDPs), such as humanin and MOTS-c, play a role in regulating energy balance and cellular stress responses. Exercise is known to improve metabolic function and stimulate MDP synthesis through mitochondria-dependent signaling pathways. Understanding these mechanisms has the potential to uncover new therapeutic targets for the treatment of metabolic diseases. Research objectives: This study sought to ascertain how physical activity affected MDPs levels. Methods: This systematic review searched four electronic databases, PubMed, Scopus, Web of Science, and ScienceDirect, for studies published between 2016 and 2025 that examined MDPs and exercise. A total of 435 records were identified. After screening according to predefined inclusion and exclusion criteria following PRISMA guidelines, nine studies were included in the final analysis. Results: Of the nine studies included in this systematic review, most reported a trend toward increased MDP levels after exercise. However, these findings should be interpreted with caution due to the limited number of studies and variations in study design, subject characteristics, and exercise protocols. Conclusion: Available evidence suggests that physical exercise has the potential to increase MDP levels, which may be associated with improved metabolic function, increased insulin sensitivity, and the efficiency of cellular energy metabolism. However, current evidence is limited, particularly in human studies. Therefore, further research, particularly controlled clinical trials and longitudinal studies, is needed to confirm these findings and evaluate MDP's potential as a therapeutic target in the prevention and management of metabolic diseases.