Proteomic Analysis of ARID1A-Deficient Ovarian Clear Cell Carcinoma Cells Reveals Differential Mitochondria ETC Subunit Abundances and Targetable Mitochondrial Pathways

Int J Mol Sci. 2025 Jun 7;26(12):5466. doi: 10.3390/ijms26125466.

Abstract

ARID1A-deficient ovarian clear cell carcinoma is a highly lethal gynecologic cancer that depends heavily on mitochondrial respiration. Our biochemical and proteomic analyses reveal that ARID1A knockout cells exhibit marked upregulation of specific subunits within mitochondrial electron transport chain (ETC) Complexes I, III, and IV. However, this upregulation does not directly translate into increased sensitivity to broad-spectrum inhibitors targeting these complexes. These findings suggest that broad-spectrum mitochondrial inhibitors may not be effective therapeutic options for ARID1A-deficient cancers. Instead, the selective inhibition of specific ETC subunits may offer a more promising approach to exploit the metabolic vulnerabilities of ARID1A-deficient cells.

Keywords: ARID1A; electron transport chain; mitochondria; ovarian clear cell carcinoma; proteomics.

MeSH terms

  • Adenocarcinoma, Clear Cell* / genetics
  • Adenocarcinoma, Clear Cell* / metabolism
  • Adenocarcinoma, Clear Cell* / pathology
  • Cell Line, Tumor
  • DNA-Binding Proteins* / deficiency
  • DNA-Binding Proteins* / genetics
  • DNA-Binding Proteins* / metabolism
  • Electron Transport Chain Complex Proteins* / genetics
  • Electron Transport Chain Complex Proteins* / metabolism
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Mitochondria* / metabolism
  • Ovarian Neoplasms* / genetics
  • Ovarian Neoplasms* / metabolism
  • Ovarian Neoplasms* / pathology
  • Proteomics* / methods
  • Transcription Factors* / deficiency
  • Transcription Factors* / genetics
  • Transcription Factors* / metabolism

Substances

  • ARID1A protein, human
  • DNA-Binding Proteins
  • Transcription Factors
  • Electron Transport Chain Complex Proteins