〔Abstract〕 Objective To investigate the protective effect of mitochondria-derived peptide MOTS-c on myocardial ischemia reperfusion injury(MIRI) in rats and elucidate its mechanism. Methods The SD rats were randomly divided into sham group, MIRI group, MOTS-c group and MOTS-c+PGC-1α inhibitor SR-18292 group(MOTS-c+SR-18292), with 10 rats in each group. The MIRI model was established by ligating the anterior descending branch of the coronary artery MOTS-c peptide(1 mg/kg), SR-18292(20 mg/kg) and equal volume concentration of 1% dimethyl sulfoxide were administeredviatail vein at 1 h before operation and immediately after operation. At 24 h after surgery, TTC staining was used to observe myocardial infarction size. HE staining was used to observe the pathological changes of myocardial tissue. TUNEL staining was used to detect myocardial apoptosis. ELISA and biochemical kits were used to measure the levels of myocardial injury markers and oxidation indicators in serum of each group. The relative copy number of mtDNA in myocardial tissues was detected by qRT-PCR. The mitochondrial biosynthesis-related protein expression levels in myocardial tissues were detected by Western blot. Results Compared with sham group, MIRI group had serious myocardial injury, myocardial infarction size and increased apoptosis level(P<0.05). The mtDNA relative copy number in myocardial tissue decreased(P<0.05). The contents of CK-MB, LDH, cTnI in serum and MDA in myocardial tissue increased(P<0.05). SOD content and PGC-1α, NRF-1 and TFAM protein expression levels in myocardial tissue decreased(P<0.05). Compared with MIRI group, myocardial injury in MOTS-c group was significantly improved, myocardial infarction size and apoptosis level decreased(P<0.05). The mtDNA relative copy number in myocardial tissue increased(P<0.05). The contents of CK-MB, LDH, cTnI in serum and MDA in myocardial tissue decreased(P<0.05). The SOD content and the expression levels of PGC-1α, NRF-1 and TFAM in myocardial tissue increased(P<0.05). Compared with MOTS-c group, the myocardial infarction size and apoptosis level of rats in MOTS-c+SR-18292 group increased(P<0.05). The mtDNA relative copy number in myocardial tissue decreased(P<0.05). The contents of CK-MB, LDH, cTnI in serum and MDA in myocardial tissue increased(P<0.05). SOD content and PGC-1α, NRF-1 and TFAM protein expression levels in myocardial tissue decreased(P<0.05). Conclusion MOTS-c peptide can improve myocardial injury in MIRI rats by promoting mitochondrial biosynthesis and inhibiting cardiomyocyte apoptosis, and its mechanism may be related to up-regulation of PGC-1α expression.