Targeting mitochondrial metabolism in clear cell carcinoma of the ovaries

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

doi:10.3390/ijms22094750

Targeting mitochondrial metabolism in clear cell carcinoma of the ovaries

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

Research output: Contribution to journal › Article › peer-review

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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 language	English (US)
Article number	4750
Journal	International journal of molecular sciences
Volume	22
Issue number	9
DOIs	https://doi.org/10.3390/ijms22094750
State	Published - May 1 2021

Bibliographical note

Funding Information:
Funding: This work was supported by the US Department of Defense Ovarian Cancer Research Program (OC160377), the Minnesota Ovarian Cancer Alliance, the Randy Shaver Cancer Research and Community Fund and the National Institute of General Medical Sciences (R01-GM130800) to M.B. This work was also supported by Cancerfonden, Vetenskapsrådet, Radiumhemmets forskningsfonder, Knut och Alice Wallenbergs Stiftelse and the Linköping Cancer Network to SL. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

Funding Information:
This work was supported by the US Department of Defense Ovarian Cancer Research Program (OC160377), the Minnesota Ovarian Cancer Alliance, the Randy Shaver Cancer Research and Community Fund and the National Institute of General Medical Sciences (R01-GM130800) to M.B. This work was also supported by Cancerfonden, Vetenskapsr?det, Radiumhemmets forskningsfonder, Knut och Alice Wallenbergs Stiftelse and the Link?ping Cancer Network to SL. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

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

Keywords

ARID1A
Mitochondria
OCCC
Ovarian cancer

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.3390/ijms22094750

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title = "Targeting mitochondrial metabolism in clear cell carcinoma of the ovaries",

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.",

keywords = "ARID1A, Mitochondria, OCCC, Ovarian cancer",

author = "Xiaonan Zhang and Mihir Shetty and Valentino Clemente and Stig Linder and Martina Bazzaro",

note = "Funding Information: Funding: This work was supported by the US Department of Defense Ovarian Cancer Research Program (OC160377), the Minnesota Ovarian Cancer Alliance, the Randy Shaver Cancer Research and Community Fund and the National Institute of General Medical Sciences (R01-GM130800) to M.B. This work was also supported by Cancerfonden, Vetenskapsr{\aa}det, Radiumhemmets forskningsfonder, Knut och Alice Wallenbergs Stiftelse and the Link{\"o}ping Cancer Network to SL. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Funding Information: This work was supported by the US Department of Defense Ovarian Cancer Research Program (OC160377), the Minnesota Ovarian Cancer Alliance, the Randy Shaver Cancer Research and Community Fund and the National Institute of General Medical Sciences (R01-GM130800) to M.B. This work was also supported by Cancerfonden, Vetenskapsr?det, Radiumhemmets forskningsfonder, Knut och Alice Wallenbergs Stiftelse and the Link?ping Cancer Network to SL. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Publisher Copyright: {\textcopyright} 2021 by the authors. Licensee MDPI, Basel, Switzerland.",

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AU - Shetty, Mihir

AU - Clemente, Valentino

AU - Linder, Stig

AU - Bazzaro, Martina

N1 - Funding Information: Funding: This work was supported by the US Department of Defense Ovarian Cancer Research Program (OC160377), the Minnesota Ovarian Cancer Alliance, the Randy Shaver Cancer Research and Community Fund and the National Institute of General Medical Sciences (R01-GM130800) to M.B. This work was also supported by Cancerfonden, Vetenskapsrådet, Radiumhemmets forskningsfonder, Knut och Alice Wallenbergs Stiftelse and the Linköping Cancer Network to SL. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Funding Information: This work was supported by the US Department of Defense Ovarian Cancer Research Program (OC160377), the Minnesota Ovarian Cancer Alliance, the Randy Shaver Cancer Research and Community Fund and the National Institute of General Medical Sciences (R01-GM130800) to M.B. This work was also supported by Cancerfonden, Vetenskapsr?det, Radiumhemmets forskningsfonder, Knut och Alice Wallenbergs Stiftelse and the Link?ping Cancer Network to SL. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

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N2 - 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.

AB - 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.

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Targeting mitochondrial metabolism in clear cell carcinoma of the ovaries

Abstract

Bibliographical note

Keywords

UN SDGs

Publisher link

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