Targeting Mitochondrial Bioenergetics as a Therapeutic Strategy for Chronic Lymphocytic Leukemia

Figure 1

Scheme of the mitochondrial electron transport chain. During the respiration process in mitochondria, electrons from the oxidized state of substrates are transported through a series of electron transport carriers (dashed arrows) located in the inner mitochondrial membrane. Electrons (e⁻) raised from NADH and FADH₂ enter the electron transport chain at Complexes I and II, respectively. The free energy is released from Complexes I, III, and IV by the gradual decrease of redox potential while electrons are passing and translocating protons (H⁺) from the matrix into the intermembrane space of mitochondria. The proton electrochemical potential gradient generated across the inner mitochondrial membrane is referred as the proton-motive force (pmf). The pmf is used to generate ATP by ATP synthase and also allows the return of protons into the matrix. The redox state of mitochondrial complexes is shown in green. Several chemical compounds (ellagic acid; acacetin; 2-ME, 2-methoxiestradiol; PEITC, β-phenylethyl isothiocyanate; VPA, valproic acid; and MCNA, metal-containing nucleoside analogues) alter the ROS generation in CLL. The comparatively darker carrier indicates a more reduced state and vice versa. Cyto c: cytochrome c; NADH: nicotinamide-adenine dinucleotide (reduced); FADH₂: flavin-adenine dinucleotide (reduced); Q: ubiquinone; ΔΨ: mitochondrial membrane potential; FCCP: carbonyl cyanide-p-trifluoromethoxyphenylhydrazone; I, II, III, and IV attribute to mitochondrial complexes; NAMPT: nicotinamide phosphoribosyltransferase; SOD1 or SOD2: superoxide dismutase 1 or 2; GPX: glutathione peroxidase.