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.
Highlights
THE ANATOMY OF COMPLEX IMammalian Complex I (NADH–quinone oxidoreductase) is the largest respiratory complex of the electron transport chain (ETC) [1]
Complex I couples electron transfer from NADH to ubiquinone to the translocation of four protons from the mitochondrial matrix to the intermembrane space [3] generating, together with the proton-pumping Complexes III and IV, the electrochemical proton gradient required for ATP synthesis [4, 5]
Complex I, the main point of entry of electrons in the ETC, controls the synthesis of precursors such as aspartate by maintaining the NAD+/NADH ratio and mitochondrial ATP synthesis by proton pumping toward the intermembrane space
Summary
Mammalian Complex I (NADH–quinone oxidoreductase) is the largest respiratory complex of the electron transport chain (ETC) [1]. It oxidizes NADH produced in the tricarboxylic acid (TCA) cycle and β-oxidation of fatty acids, regenerating the NAD+ levels in the mitochondrial matrix [2]. Complex I couples electron transfer from NADH to ubiquinone to the translocation of four protons from the mitochondrial matrix to the intermembrane space [3] generating, together with the proton-pumping Complexes III and IV, the electrochemical proton gradient required for ATP synthesis [4, 5]. Complex I is a L-shaped assembly (Figure 1A) composed of a hydrophilic peripheral arm, which contains the redox centers involved in electron transfer, and a membrane arm containing the proton-translocating machinery [6, 7].
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