Introduction

Mitochondria are organelles produced by archaea that are required for the production of ATP (1). The organism exhibits semi-autonomous genetic systems, independent genomes, and unique genetic codes that are similar to those found in bacteria (2). Recently, a short open reading frame (sORF) encoded in the mitochondrial genome has been discovered (3, 4). These sORF produce bioactive peptides, collectively known as mitochondrial-derived peptides (MDP), which have a wide range of physiological functions and can explain how mitochondria communicate within and between cells in a specific disease environment (5). Mitochondrial-derived peptides may answer the key biological problems that have plagued the field for decades (such as mitochondrial-nuclear communication, metabolic dysfunction, etc.) (6). Whether in the form of mitochondrial-derived peptide itself or in terms of sORF, mitochondrial-derived peptide is suitable for research as a therapeutic agent (1).

Studies discovered mitochondrial-derived peptide called MOTS-c has been shown to significantly reduce the level of pro-inflammatory factors in mice and increase anti-inflammatory factors and insulin-stimulated glucose treatment rates, as well as glucose homeostasis (7–9). Furthermore, human studies showed that exercise increased MOTS-c levels in skeletal muscle and blood circulation, indicating that MOTS-c is a mitochondrial-derived peptide induced by skeletal muscle exercise (9, 10). Additionally, more and more studies have revealed the importance of MOTS-c in regulating obesity and diabetes (11, 12), longevity (13), and cardiovascular disease (14). Specifically, this paper discusses the application of mitochondrial-derived peptides, including MOTS-c, in the treatment of diseases and anticipates the future development direction of MOTS-c combining synthetic biology to provide new ideas on how it can be developed and applied.

Physiological function of MOTS-c

MOTS-c, one of the newly discovered sORF-encoded peptides, is a 16-amino acid polypeptide encoded by the mitochondrial 12S rRNA gene and localized to mitochondria under resting conditions ( Figure 1 ) (7). Translation of MOTS-c peptide occurs exclusively in the cytoplasm, as mitochondrial translation, using the mitochondria-specific genetic code, results in tandem codons. As a result, the polyadenylated transcript would be exported from the mitochondria. The sequence of MOTS-c peptides, especially the first 11 residues, is highly conserved among 14 species, including humans and mice