Page 62 - JCTR-11-5

Journal of Clinical and
Translational Research Metabolism of healthy and leukemic stem cells

Figure 2. LSC metabolic rewiring. A graphical depiction of an LSC located within the hypoxic BM niche. 13,14 Here, LSCs rely heavily on upregulated FAO,
OXPHOS, and ATP production for self-renewal and survival. 84,85 Complex I of the ETC plays an essential role in driving ATP production by acting as the
primary site for NADH oxidation and electron (e ) entry into the ETC. From here, electrons are transferred to coenzyme ubiquinone (Q), while protons
87
−
(H ) are simultaneously pumped across the inner mitochondrial membrane, generating the proton gradient necessary for ATP synthesis. During this
+
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process, LSCs also exhibit elevated OXPHOS activity and increased levels of ROS. To enhance mitochondrial efficiency and sustain these elevated rates of
25
OXPHOS, LSCs rewire conventional metabolic programs and mitigate elevated ROS levels through increased antioxidant buffering, which enables them
to tolerate ROS at levels conductive to self-renewal while exhibiting oxidative resistance. 14,75,83,88 LSCs also remodel their microenvironment, leading to the
increased expression of ABC transporters (e.g., ABCB1, ABCC1, and ABCG2), resulting in chemoresistance. 85,86
Abbreviations: BM: Bone marrow; ETC: Electron transport chain; FADH: Flavin adenine dinucleotide; FADH : Reduced form of flavin adenine
2
dinucleotide; FAO: Fatty acid oxidation; H O: Water; H O : Hydrogen peroxide; LSC: Leukemia stem cell; NADH: Nicotinamide adenine dinucleotide;
2
2
2
OXPHOS: Oxidative phosphorylation; ROS: Reactive oxygen species; SOD1/2: Superoxide dismutase ½.
fuel mitochondrial respiration. 14,25 One such pathway that components such as eukaryotic translation initiation factor
further differentiates HSCs from LSCs is FAO. In LSCs, 2α and the stress-adaptive activating transcription factor 4
FAO is upregulated to support mitochondrial respiration reduce ROS-induced apoptosis, maintain redox balance,
and promote chemoresistance. 14,26 To sustain this elevated and support mitochondrial metabolism. 92-94 This process
FAO activity, LSCs highly express Cluster of Differentiation also enhances resistance to therapeutic intervention and
(CD)-36 for increased fatty acid transport and lipid promotes the long-term persistence of LSCs, serving as a
scavenging and rely on carnitine palmitoyltransferase critical mediator of survival. 92,93
1A-driven lipid oxidation. 85,86 AML LSCs exhibit increased These fundamental differences in metabolic regulation
carnitine palmitoyltransferase 1A expression to facilitate demonstrate how LSCs are uniquely equipped for survival.
long-chain fatty acid breakdown and express CD36 when Despite this, the notion that FAO is critical to LSC survival
localized to adipocyte-rich niches, enabling the scavenging remains under scrutiny. AML LSCs exhibit a distinct
of extracellular lipids. 85,86 Notably, LSCs tolerate moderate metabolic phenotype compared with both normal HSCs
levels of intracellular ROS by exhibiting enhanced oxidative and bulk leukemia blasts, characterized by a dependence on
resistance, which fuels proliferation without triggering mitochondrial respiration rather than glycolysis. Previous
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oxidative damage, in contrast to the ROS sensitivity of studies have demonstrated that AML LSCs maintain low
normal quiescent HSCs. 5,14,88 ROS levels while displaying elevated oxidative metabolism
One mechanism that enables LSC tolerance to ROS is the and adenosine monophosphate-activated protein kinase
integrated stress response (ISR). 91-93 The ISR is a conserved (AMPK) activation. These features are consistent with
95
cellular pathway that balances innate biological processes, a mitochondria-centric bioenergetic program. Similarly,
such as protein synthesis and gene expression, in response another study showed that the activation of the signal
to stressors such as ROS-induced oxidative damage, transducer and activator of transcription 3 (STAT3)–
nutrient deprivation, and mitochondrial dysfunction. 91,92 MYC axis enhances SLC1A5-mediated glutamine import,
In LSCs, the ISR sustains cell survival under metabolic and thereby reinforcing TCA cycle flux and mitochondrial
therapeutic pressure. Phosphorylation and activation of metabolism. While LSCs retain functional glycolysis
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Volume 11 Issue 5 (2025) 56 doi: 10.36922/JCTR025320053