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

Yadong Yin1, Yujie Li2, Boyi Ma1

  • 1Department of Gynaecology and Obstetrics, Xijing Hospital, Air Force Medical University, Xi'an, 710032, China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|September 25, 2024
PubMed

Insights

Reduced levels of MOTS-c peptide in ovarian cancer (OC) correlate with poor prognosis. This study reveals MOTS-c peptide

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • Mitochondrial-nuclear communication is crucial for cellular homeostasis.
  • Mitochondria-derived ORFan peptide (MOTS-c) is a potential retrograde mitochondrial signal.
  • The role of MOTS-c in cancer, particularly ovarian cancer (OC), remains largely uninvestigated.

Purpose of the Study:

  • To investigate the role of MOTS-c in ovarian cancer (OC) tumorigenesis.
  • To explore the therapeutic potential of MOTS-c in OC treatment.

Main Methods:

  • Quantification of MOTS-c levels in OC patient serum and tissues.
  • In vitro assays to assess the effects of exogenous MOTS-c on OC cell proliferation, migration, invasion, cell cycle, and apoptosis.
  • Mechanistic studies involving ubiquitination, proteasomal degradation, and protein-protein interactions (MOTS-c, LARS1, USP7).
  • In vivo anti-tumor efficacy and toxicity studies of MOTS-c in OC models.

Main Results:

  • MOTS-c levels are significantly reduced in OC patient serum and tumors, correlating with poor prognosis.
  • Exogenous MOTS-c inhibits OC cell proliferation, migration, and invasion, while inducing cell cycle arrest and apoptosis.
  • MOTS-c promotes LARS1 ubiquitination and proteasomal degradation by interfering with USP7-mediated deubiquitination.
  • LARS1 is upregulated and exhibits oncogenic functions in OC.
  • MOTS-c demonstrates significant anti-tumor effects in vivo without systemic toxicity.

Conclusions:

  • This study establishes a critical role for MOTS-c in ovarian cancer (OC).
  • Reduced MOTS-c levels are linked to poor OC prognosis.
  • MOTS-c exhibits potent anti-tumor activity against OC through LARS1 regulation.
  • MOTS-c presents a promising therapeutic target for ovarian cancer (OC) treatment.
Keywords:
LARS1MOTS‐cUSP7ovarian cancerubiquitination

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