Bioenergetic and Proteomic Profiling of ARID1A-Deficient Ovarian Clear Cell Carcinoma under Metabolic Challenge
ARID1A loss is associated with increased mitochondrial respiration in ovarian clear cell carcinoma (OCCC), but whether this phenotype is maintained under metabolic challenge remains unclear. Here, we examined mitochondrial function and electron transport chain (ETC) protein abundance in isogenic ARID1A wild-type (WT) and ARID1A-knockout (KO) OCCC cells cultured under physiological glucose, galactose, or the Complex I inhibitor IACS-010759. Across all conditions, KO cells maintained higher basal, ATP-linked, and maximal respiration, greater spare respiratory capacity, and higher coupling efficiency than WT cells, despite lower steady-state ATP levels. In human OCCC tumors, ARID1A-negative cases showed a higher bioenergetic cellular (BEC) index than ARID1A-positive cases, and high BEC was associated with poorer cancer-specific survival. Quantitative proteomics revealed a trend toward higher ETC complex abundance in KO cells, although whole-complex differences did not reach statistical significance. ARID1A loss was associated with selective increases in Complex III and V proteins, whereas metabolic challenge was associated with increases in Complex I and IV proteins. Together, these findings show that the ARID1A-associated mitochondrial phenotype persists across distinct metabolic challenges and is not explained simply by coordinated increases in ETC protein abundance. The association of mitochondrial bioenergetics with clinical outcomes further supports its relevance in human OCCC.