Targeting mitochondrial metabolism in clear cell carcinoma of the ovaries

Xiaonan Zhang, Mihir Shetty, Valentino Clemente, Stig Linder, Martina Bazzaro

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Ovarian clear cell carcinoma (OCCC) is a rare but chemorefractory tumor. About 50% of all OCCC patients have inactivating mutations of ARID1A, a member of the SWI/SNF chromatin-remodeling complex. Members of the SWI/SNF remodeling have emerged as regulators of the energetic metabolism of mammalian cells; however, the role of ARID1A as a modulator of the mitochondrial metabolism in OCCCs is yet to be defined. Here, we show that ARID1A loss results in increased mitochondrial metabolism and renders ARID1A-mutated cells increasingly and selectively dependent on it. The increase in mitochondrial activity following ARID1A loss is associated with increase in c-Myc expression and increased mitochondrial number and reduction of their size consistent with a higher mitochondrial cristae/outer membrane ratio. Significantly, preclinical testing of the complex I mitochondrial inhibitor IACS-010759 showed it extends overall survival in a preclinical model of ARID1A-mutated OCCC. These findings provide for the targeting mitochondrial activity in ARID1A-mutated OCCCs.

Original languageEnglish (US)
Article number4750
JournalInternational journal of molecular sciences
Volume22
Issue number9
DOIs
StatePublished - May 1 2021

Bibliographical note

Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

  • ARID1A
  • Mitochondria
  • OCCC
  • Ovarian cancer

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