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Decreased Mitochondrial DNA Content Drives OXPHOS Dysregulation in Chromophobe Renal Cell Carcinoma

Yi Xiao1,2, Rosanna Clima3,4, Jonas Busch5

  • 1Max Planck Institute for Molecular Genetics, Berlin, Germany.

Cancer Research
|July 23, 2020
PubMed

Insights

Chromophobe renal cell carcinoma (chRCC) exhibits distinct oxidative phosphorylation (OXPHOS) mechanisms compared to renal oncocytoma. Reduced mitochondrial DNA content, not Complex I mutations, causes OXPHOS dysfunction in chRCC, offering potential diagnostic markers.

Area of Science:

  • * Renal cell carcinoma research
  • * Cancer genomics
  • * Mitochondrial biology

Background:

  • * Chromophobe renal cell carcinoma (chRCC) and renal oncocytoma are rare, similar kidney tumors.
  • * Complex I (CI) mutations impact oxidative phosphorylation (OXPHOS) in renal oncocytoma but are less common in chRCC.
  • * The role of OXPHOS and CI mutations in chRCC pathogenesis is largely unknown.

Purpose of the Study:

  • * To investigate the role of mitochondrial alterations and OXPHOS dysfunction in chRCC.
  • * To compare the molecular mechanisms of OXPHOS between chRCC and renal oncocytoma.
  • * To identify potential diagnostic markers for chRCC.

Main Methods:

  • * Proteome and metabolome profiling of chRCC tissue specimens.
  • * Mitochondrial whole-exome sequencing.
  • * Multiomic analysis integrating proteomic, metabolomic, and genomic data.

Main Results:

  • * chRCC displayed downregulated electron transport chain (ETC) components, differing from renal oncocytoma.
  • * Decreased mitochondrial (mt)DNA content, not CI mutations, was the primary cause of reduced OXPHOS in chRCC.
  • * Glutathione (GSH) was upregulated in chRCC due to reduced expression of GSH-degrading proteins.
  • * Negative correlation observed between protein and transcript levels of nuclear-encoded ETC subunits.

Conclusions:

  • * Distinct mechanisms underlie OXPHOS dysfunction in chRCC versus renal oncocytoma.
  • * Mitochondrial DNA content is a key factor in chRCC OXPHOS impairment.
  • * ETC complex subunit expression levels can serve as diagnostic markers to differentiate chRCC from renal oncocytoma.

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