Bioenergetic and Proteomic Profiling of ARID1A-Deficient Ovarian Clear Cell Carcinoma under Metabolic…

Abstract

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.

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BibTeX

@misc{ismail2026bioenergetic,
  title = {{Bioenergetic and Proteomic Profiling of ARID1A-Deficient Ovarian Clear Cell Carcinoma under Metabolic Challenge}},
  author = {Harith A. Ismail and Kristina Dankova and Trudy J. Philips and Brittany R. Davidson and Carly A. I. Twigg and Karthik Selvaraj and Valentino Clemente and Giancarlo Curci and Beatrice Dallan and Mihir Shetty and Asumi Hoshino and Pádraig D’Arcy and Francesco Nicoli and Shijia Zhu and Stefani N. Thomas and Martina Bazzaro},
  howpublished = {bioRxiv},
  year = {2026},
  month = oct,
  doi = {10.64898/2026.10.09.757928},
  url = {https://www.biorxiv.org/content/10.64898/2026.10.09.757928v1},
  note = {CC BY},
}

RIS

TY  - UNPB
TI  - Bioenergetic and Proteomic Profiling of ARID1A-Deficient Ovarian Clear Cell Carcinoma under Metabolic Challenge
AU  - Harith A. Ismail
AU  - Kristina Dankova
AU  - Trudy J. Philips
AU  - Brittany R. Davidson
AU  - Carly A. I. Twigg
AU  - Karthik Selvaraj
AU  - Valentino Clemente
AU  - Giancarlo Curci
AU  - Beatrice Dallan
AU  - Mihir Shetty
AU  - Asumi Hoshino
AU  - Pádraig D’Arcy
AU  - Francesco Nicoli
AU  - Shijia Zhu
AU  - Stefani N. Thomas
AU  - Martina Bazzaro
PY  - 2026
DA  - 2026/10/09
PB  - bioRxiv
DO  - 10.64898/2026.10.09.757928
UR  - https://www.biorxiv.org/content/10.64898/2026.10.09.757928v1
AB  - 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.
SN  - 2692-8205
ER  -

Abstract

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