Researchers from University of Pennsylvania have found that the defect of mitochondria play a very important role in the transition from normal cells to cancer cells. This study was published in Oncogene.

In keeping with the Warburg hypothesis proposing aerobic glycolysis as an important factor in tumor growth, altered mitochondrial function and increased utilization of glucose for energy are hallmarks of many proliferation tumors. A number of studies have shown defective mitochondrial electron transport chain complexes (ETC) in human cancers.

Loss of mtDNA copy number has been reported in breast, prostate, hepatocellular and lung cancers. In this study, researchers have shown that partial mtDNA depletion mediates tumorigenesis by activating a Ca²⁺-Calcineurin (Cn)-dependent retrograde signaling. The onset of this signaling is characterized by loss of mitochondrial membrane potential.

In this study, scientists show that silencing of subunits IVi1 or Vb of CcO induces a mitochondrial retrograde signaling, which largely mimics the signaling that they reported in mtDNA-depleted cells. The cells acquired invasiveness and showed loss of contact inhibition generally observed in tumor cells. There was increased expression of marker genes of the Ca²⁺/Cn signaling pathway.

As expected, these cells with disrupted CcO complex showed many features of ‘Warburg Effect,’ including increased dependence on glycolysis and invasive behavior in otherwise non-tumorigenic C2C12 skeletal myoblasts. Similarly, in cell lines derived from esophageal and breast cancers, loss of cytochrome oxidase increased invasiveness. Strikingly, in C2C12 cells, these changes were reversed by reconstituting subunit IVi1-silenced cells with wild-type CcOIVi1 cDNA, thus establishing a novel role of this ETC component in the tumorigenic process.