Mitochondrial NDUFS3 regulates the ROS-mediated onset of metabolic switch in transformed cells

Sonal Suhane, Hirotaka Kanzaki, Vaithilingaraja Arumugaswami, Ramachandran Murali, V. Krishnan Ramanujan

Research output: Contribution to journalArticlepeer-review

25 Citations (Scopus)

Abstract

Aerobic glycolysis in transformed cells is an unique metabolic phenotype characterized by a hyperactivated glycolytic pathway even in the presence of oxygen. It is not clear if the onset of aerobic glycolysis is regulated by mitochondrial dysfunction and, if so, what the metabolic windows of opportunity available to control this metabolic switch (mitochondrial to glycolytic) landscape are in transformed cells. Here we report a genetically-defined model system based on the gene-silencing of a mitochondrial complex I subunit, NDUFS3, where we demonstrate the onset of metabolic switch in isogenic human embryonic kidney cells by differential expression of NDUFS3. By means of extensive metabolic characterization, we demonstrate that NDUFS3 gene silencing systematically introduces mitochondrial dysfunction thereby leading to the onset of aerobic glycolysis in a manner dependent on NDUFS3 protein levels. Furthermore, we show that the sustained imbalance in free radical dynamics is a necessary condition to sustain the observed metabolic switch in cell lines with the most severe NDUFS3 suppression. Together, our data reveal a novel role for mitochondrial complex I subunit NDUFS3 in regulating the degree of mitochondrial dysfunction in living cells, thereby setting a "metabolic threshold" for the observation of aerobic glycolysis phenotype within the confines of mitochondrial dysfunction.

Original languageEnglish
Pages (from-to)295-305
Number of pages11
JournalBiology Open
Volume2
Issue number3
DOIs
Publication statusPublished - Mar 15 2013
Externally publishedYes

Keywords

  • Aerobic glycolysis
  • Metabolic switch
  • Mitochondrial complex I
  • Mitochondrial dysfunction
  • NDUFS3
  • Reactive oxygen species

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

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