Targeting Mitochondrial Bioenergetics as a Therapeutic Strategy for Chronic Lymphocytic Leukemia

Abstract

Altered cellular metabolism is considered a hallmark of cancer and is fast becoming an avenue for therapeutic intervention. Mitochondria have recently been viewed as an important cellular compartment that fuels the metabolic demands of cancer cells. Mitochondria are the major source of ATP and metabolites necessary to fulfill the bioenergetics and biosynthetic demands of cancer cells. Furthermore, mitochondria are central to cell death and the main source for generation of reactive oxygen species (ROS). Overall, the growing evidence now suggests that mitochondrial bioenergetics, biogenesis, ROS production, and adaptation to intrinsic oxidative stress are elevated in chronic lymphocytic leukemia (CLL). Hence, recent studies have shown that mitochondrial metabolism could be targeted for cancer therapy. This review focuses the recent advancements in targeting mitochondrial metabolism for the treatment of CLL.

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.

Figure 2

Bioenergetics profile in normal B lymphocytes and primary CLL cells. General scheme of bioenergetics parameters during mitochondrial stress test is shown. Sequential injections of oligomycin, FCCP, rotenone, and antimycin A measure basal respiration (green), ATP-linked oxygen consumption (yellow), proton leak (pink), maximal respiration (orange), reserve respiratory capacity (gold: maximal respiration—basal respiration), and nonmitochondrial respiration (blue). Dashed lines indicate OCR for the portion of each defined parameter. CLL, chronic lymphocytic leukemia lymphocytes, (black line) and normal B-lymphocytes (red line). The comparison of mitochondrial of bioenergetics between CLL and normal B-lymphocytes shown in this figure is adapted based on the results demonstrated by Jitschin et al. [29].