Mitochondrial‐Derived Peptide MOTS‐c Suppresses Ovarian Cancer Progression by Attenuating USP7‐Mediated LARS1 Deubiquitination

Abstract Mitochondrial‐nuclear communication plays a vital role in maintaining cellular homeostasis. MOTS‐c, a short peptide derived from the 12S rRNA of mitochondrial DNA, has been suggested as a retrograde mitochondrial signal. Although recent clinical studies have suggested a possible link between MOTS‐c and human cancer, the role of MOTS‐c in tumorigenesis has yet to be investigated. Here, MOTS‐c levels are found to be reduced in both serum and tumor tissues from ovarian cancer (OC) patients, which are associated with poor patients’ prognosis. Exogenous MOTS‐c inhibits the proliferation, migration and invasion of OC cells, and induces cell cycle arrest and apoptosis. Mechanistically, MOTS‐c interacts with LARS1 and promotes its ubiquitination and proteasomal degradation. In addition, USP7 was identified as a deubiquitinase of LARS1, and MOTS‐c can attenuates USP7‐mediated LARS1 deubiquitination by competing with USP7 for binding to LARS1. Besides, LARS1 was found to be increased and play an important oncogenic function in OC. More importantly, MOTS‐c displays a marked anti‐tumor effect on OC growth without systemic toxicity in vivo. In conclusion, this study reveals a crucial role of MOTS‐c in OC and provides a possibility for MOTS‐c as a therapeutic target for the treatment of this manlignacy.