Mitochondrial metabolism as a potential therapeutic target in myeloid leukaemia

Abstract

While the understanding of the genomic aberrations that underpin chronic and acute myeloid leukaemia (CML and AML) has allowed the development of therapies for these diseases, limitations remain. These become apparent when looking at the frequency of treatment resistance leading to disease relapse in leukaemia patients. Key questions regarding the fundamental biology of the leukaemic cells, such as their metabolic dependencies, are still unresolved. Even though a majority of leukaemic cells are killed during initial treatment, persistent leukaemic stem cells (LSCs) and therapy-resistant cells are still not eradicated with current treatments, due to various mechanisms that may contribute to therapy resistance, including cellular metabolic adaptations. In fact, recent studies have shown that LSCs and treatment-resistant cells are dependent on mitochondrial metabolism, hence rendering them sensitive to inhibition of mitochondrial oxidative phosphorylation (OXPHOS). As a result, rewired energy metabolism in leukaemic cells is now considered an attractive therapeutic target and the significance of this process is increasingly being recognised in various haematological malignancies. Therefore, identifying and targeting aberrant metabolism in drug-resistant leukaemic cells is an imperative and a relevant strategy for the development of new therapeutic options in leukaemia. In this review, we present a detailed overview of the most recent studies that present experimental evidence on how leukaemic cells can metabolically rewire, more specifically the importance of OXPHOS in LSCs and treatment-resistant cells, and the current drugs available to target this process. We highlight that uncovering specific energy metabolism dependencies will guide the identification of new and more targeted therapeutic strategies for myeloid leukaemia.

Fig. 1. Cellular energy metabolism: Linkage of OXPHOS to catabolic pathways for glucose, fatty acids, and glutamine.

Cells use OXPHOS to generate ATP, through the interlinkage of TCA cycle and electron transport chain (ETC). TCA cycle supplies NADH and FADH₂ to the ETC. Electrons are donated by NADH to complex I and by FADH₂ to complex II, then transferred to coenzyme Q, to complex III, to cytochrome c and finally to complex IV. This electron transport allows a series of oxidation and reduction reactions within complexes I, II and IV, which in turns allows these complexes to transfer hydrogen protons from inside the mitochondria to the mitochondrial intermembrane space. The accumulation of protons in this space creates a difference in the charge between the inner mitochondria and its intermembrane space. This mitochondrial potential allows protons to flow back into the mitochondria through complex V, providing the energy to bond an inorganic phosphate to a molecule of ADP, producing ATP. Glycolysis is the metabolic process in which glucose is converted into pyruvate, which can then convert pyruvate into acetyl-CoA used in TCA cycle, hence in OXPHOS. One molecule of fructose-6P yields two glyceraldehyde 3-P, thus, one molecule of glucose can yield two molecules of pyruvate. Fatty acid metabolism can also supply the TCA cycle with acetyl-CoA through the fatty acid β-oxidation. Glutamine metabolism is the process in which glutaminase (GLS) converts glutamine to glutamate, which can then be passed into the mitochondrion through the glutamate shuttle and can be converted into α-ketoglutarate, further supplying TCA cycle and enhance OXPHOS activity. (GLS: glutaminase; IDH2: isocitrate dehydrogenase: Lactate DH: lactate dehydrogenase; PFK: phosphofructokinase).

Fig. 2. The specific activity of OXPHOS inhibitors tested in the clinic in leukaemia.

Representation of mechanism of action of each compound and their clinical trial status (Table 1). (GLS: glutaminase; IDH2: isocitrate dehydrogenase; mtDNA: mitochondrial DNA; mtRibosomes: mitochondrial ribosomes; PDH: pyruvate dehydrogenase).