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Updated: Nov 6, 2025
Preparation of Mitochondria from Ovarian Cancer Tissues and Control Ovarian Tissues for Quantitative Proteomics Analysis
Published on: November 18, 2019
Targeting Mitochondrial Metabolism in Clear Cell Carcinoma of the Ovaries
Xiaonan Zhang1,2, Mihir Shetty2, Valentino Clemente2
1Department of Immunology, Genetics and Pathology, Uppsala University, 75185 Uppsala, Sweden.
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.
Insights
Loss of ARID1A in ovarian clear cell carcinoma increases mitochondrial metabolism, creating a dependency. Targeting this mitochondrial activity with IACS-010759 shows promise in preclinical models.
Area of Science:
- Oncology
- Cell Biology
- Biochemistry
Background:
- Ovarian clear cell carcinoma (OCCC) is a rare, chemorefractory cancer.
- Approximately 50% of OCCC cases involve inactivating mutations in ARID1A, a SWI/SNF chromatin-remodeling complex component.
- The role of ARID1A in regulating mitochondrial metabolism in OCCC is largely undefined.
Purpose of the Study:
- To investigate the role of ARID1A in modulating mitochondrial metabolism in OCCC.
- To determine if ARID1A-mutated OCCC cells exhibit specific dependencies on mitochondrial activity.
- To evaluate the therapeutic potential of targeting mitochondrial metabolism in ARID1A-mutated OCCC.
Main Methods:
- Analysis of ARID1A's role in mitochondrial metabolism in OCCC cells.
- Assessment of cellular dependency on mitochondrial activity following ARID1A loss.
- Evaluation of c-Myc expression, mitochondrial number, size, and cristae/outer membrane ratio.
- Preclinical testing of the mitochondrial inhibitor IACS-010759 in an ARID1A-mutated OCCC model.
Main Results:
- ARID1A loss leads to increased mitochondrial metabolism and selective cellular dependency.
- Increased mitochondrial activity correlates with elevated c-Myc expression.
- ARID1A loss is associated with increased mitochondrial number, reduced size, and a higher cristae/outer membrane ratio.
- The complex I inhibitor IACS-010759 significantly improved overall survival in a preclinical model of ARID1A-mutated OCCC.
Conclusions:
- ARID1A loss fundamentally alters mitochondrial metabolism in OCCC.
- ARID1A-mutated OCCC exhibits a critical dependence on enhanced mitochondrial activity.
- Targeting mitochondrial activity, specifically complex I, represents a potential therapeutic strategy for ARID1A-mutated OCCC.
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