Mitochondrial supercomplex assembly promotes breast and endometrial tumorigenesis by metabolic alterations and enhanced hypoxia tolerance

Nat Commun. 2019 Sep 11;10(1):4108. doi: 10.1038/s41467-019-12124-6.

Abstract

Recent advance in cancer research sheds light on the contribution of mitochondrial respiration in tumorigenesis, as they efficiently produce ATP and oncogenic metabolites that will facilitate cancer cell growth. Here we show that a stabilizing factor for mitochondrial supercomplex assembly, COX7RP/COX7A2L/SCAF1, is abundantly expressed in clinical breast and endometrial cancers. Moreover, COX7RP overexpression associates with prognosis of breast cancer patients. We demonstrate that COX7RP overexpression in breast and endometrial cancer cells promotes in vitro and in vivo growth, stabilizes mitochondrial supercomplex assembly even in hypoxic states, and increases hypoxia tolerance. Metabolomic analyses reveal that COX7RP overexpression modulates the metabolic profile of cancer cells, particularly the steady-state levels of tricarboxylic acid cycle intermediates. Notably, silencing of each subunit of the 2-oxoglutarate dehydrogenase complex decreases the COX7RP-stimulated cancer cell growth. Our results indicate that COX7RP is a growth-regulatory factor for breast and endometrial cancer cells by regulating metabolic pathways and energy production.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Breast Neoplasms / genetics
  • Breast Neoplasms / pathology*
  • Carcinogenesis / metabolism
  • Carcinogenesis / pathology*
  • Cell Line, Tumor
  • Cell Proliferation
  • Electron Transport Complex IV / metabolism
  • Endometrial Neoplasms / genetics
  • Endometrial Neoplasms / metabolism*
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Hypoxia / metabolism
  • Hypoxia / pathology*
  • Ketoglutarate Dehydrogenase Complex / metabolism
  • Mitochondria / metabolism*
  • Oxygen Consumption
  • Reactive Oxygen Species / metabolism

Substances

  • Reactive Oxygen Species
  • Ketoglutarate Dehydrogenase Complex
  • Electron Transport Complex IV