The Mitochondrial Complex(I)ty of Cancer

Abstract

Recent evidence highlights that the cancer cell energy requirements vary greatly from normal cells and that cancer cells exhibit different metabolic phenotypes with variable participation of both glycolysis and oxidative phosphorylation. NADH-ubiquinone oxidoreductase (Complex I) is the largest complex of the mitochondrial electron transport chain and contributes about 40% of the proton motive force required for mitochondrial ATP synthesis. In addition, Complex I plays an essential role in biosynthesis and redox control during proliferation, resistance to cell death, and metastasis of cancer cells. Although knowledge about the structure and assembly of Complex I is increasing, information about the role of Complex I subunits in tumorigenesis is scarce and contradictory. Several small molecule inhibitors of Complex I have been described as selective anticancer agents; however, pharmacologic and genetic interventions on Complex I have also shown pro-tumorigenic actions, involving different cellular signaling. Here, we discuss the role of Complex I in tumorigenesis, focusing on the specific participation of Complex I subunits in proliferation and metastasis of cancer cells.

Keywords: anticancer agents; cancer cells; electron transport chain; metastasis; mitochondrial respiration.

Figure 1

Structure of mammalian respiratory Complex I and role during tumorigenesis. (A) Structure of mammalian Complex I (PDB: 4UQ8), indicating the sites involved in the NADH oxidoreductase activity (NADH oxidation and ubiquinone reduction) in the peripheral arm and in the proton translocation in the membrane arm. A list of the core and accessory subunits that compose the mitochondrial Complex I is shown. (B) Complex I signaling involved in the supporting of tumor growth, resistance to cell death, and promoting of metastasis.