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RCCD1 promotes breast carcinogenesis through regulating hypoxia-associated mitochondrial homeostasis.

Yani Peng1, Xiaoping Liu1, Xinhua Liu2

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Oncogene
|October 31, 2023
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Summary

Regulator of chromosome condensation domain-containing protein 1 (RCCD1) unexpectedly localizes to mitochondria, impacting mitochondrial DNA transcription and reactive oxygen species production. This mitochondrial role of RCCD1 promotes breast cancer cell survival and tumor growth.

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Area of Science:

  • Mitochondrial biology
  • Cancer research
  • Molecular cell biology

Background:

  • Regulator of chromosome condensation domain-containing protein 1 (RCCD1) was previously linked to chromosome segregation.
  • RCCD1 has been implicated as a potential driver in breast cancer development.
  • The precise cellular functions and localization of RCCD1 beyond its known nuclear roles were unclear.

Purpose of the Study:

  • To investigate the unexpected mitochondrial localization of RCCD1.
  • To elucidate the role of RCCD1 in mitochondrial function and homeostasis.
  • To determine the impact of RCCD1's mitochondrial function on breast cancer progression.

Main Methods:

  • Immunofluorescence and cell fractionation to determine RCCD1 localization.
  • Co-immunoprecipitation assays to identify interacting partners within mitochondria.
  • Analysis of mitochondrial DNA (mtDNA) transcription, oxidative phosphorylation, and reactive oxygen species (ROS) production.
  • In vitro cell proliferation assays and in vivo tumor growth studies in mouse models.
  • Analysis of RCCD1 expression levels in human breast carcinoma samples.

Main Results:

  • RCCD1 was found to reside in the mitochondrial matrix, interacting with the mitochondrial contact site/cristae organizing system (MICOS) and mtDNA.
  • RCCD1 regulates mtDNA transcription, oxidative phosphorylation, and ROS production.
  • RCCD1 upregulation under hypoxia decreases ROS and apoptosis, promoting cancer cell survival.
  • RCCD1 overexpression enhances breast cancer cell proliferation in vitro and tumor growth in vivo.
  • Elevated RCCD1 expression in breast carcinomas correlates with aggressive phenotypes and poor patient survival.

Conclusions:

  • RCCD1 possesses a novel function in regulating mitochondrial homeostasis.
  • Dysregulation of RCCD1's mitochondrial role contributes to breast cancer pathogenesis.
  • RCCD1 represents a potential therapeutic target for breast cancer treatment.