Page 61 - JCTR-11-5

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

function and biogenesis upon stimulation. 5,9,10 Disruption linked to elevations in FAO and OXPHOS. 84,85 However,
of this dynamic equilibrium can impair mitochondrial the intrinsic organization of mitochondria in LSCs and
function and lead to stem cell exhaustion or aberrant their contribution to chemoresistance remain to be fully
differentiation. 10 understood. 85,86
Fusion allows mitochondria to merge and share 3.1. Shared and divergent pathways between HSCs
mitochondrial contents, including DNA, proteins, and and LSCs
metabolites, thereby compensating for damaged or
inefficient mitochondrial function and maximizing the Quiescent HSCs and oncogenic LSCs both rely primarily
ratio of metabolically healthy mitochondria. In contrast, on core metabolic pathways, including glycolysis and
9,10
5,14
mitochondrial biogenesis provides mitochondria with FAO, to maintain self-renewal and survival. However,
the ability to produce more mitochondria, while fission they differ in how these pathways are regulated. In HSCs,
enables division during cell proliferation or isolates metabolism is tightly regulated by numerous extrinsic and
damaged mitochondrial segments for removal through intrinsic niche factors to preserve quiescence and genomic
5,14
mitophagy. A key consequence of improper regulation integrity, as discussed in previous sections. Moreover,
9,10
of mitochondrial dynamics is the accumulation of excess these quiescent stem cells are predominantly glycolytic,
ROS beyond the levels needed for HSC stimulation. The express high levels of glycolytic enzymes, and suppress
physiology and metabolic state of mitochondria influence mitochondrial membrane potential to minimize ROS
their morphology, dynamics, and turnover rate, which production and prevent premature HSC activation. 5,14,89
directly affect ROS production. Although moderate In contrast, LSCs rewire these metabolic programs
9,10
ROS levels are required to drive HSCs out of quiescence, to enhance mitochondrial efficiency, thereby sustaining
elevated ROS levels can induce DNA damage, impair elevated rates of oxidative metabolism, which may
self-renewal, promote senescence, or induce oncogenic ultimately facilitate resistance to metabolic or therapeutic
80
transformation. 80,81 stress. For example, LSC mitochondria depend primarily
25
To mitigate excessive oxidative stress, cells deploy on components of the ETC to facilitate the generation of
a selective form of autophagy termed “mitophagy.” ATP and regulate redox balance. 14,25 In chronic myeloid
Mitophagy is a process by which the cell selectively leukemia (CML), LSCs exhibit elevated OXPHOS activity
degrades damaged or dysfunctional mitochondria. 10,82 and increased catabolism of TCA cycle metabolites. An
It also prevents the buildup of ROS and eliminates increase in mitochondrial respiratory flux to generate
dysfunctional mitochondria, thereby enabling HSCs to ATP sensitizes these cells to Complex I inhibition by
90
maintain homeostasis during quiescence and preserve phenformin. Complex I, or NADH dehydrogenase,
a healthy mitochondrial population in anticipation of is a central regulatory step within the mitochondrial
activation. 10,82 In addition, redox buffering systems, largely respiratory chain and a primary site of electron entry
+ 87
fueled by nicotinamide adenine dinucleotide phosphate into the ETC through oxidation of NADH to NAD .
(NADPH) reducing power, help to buffer accumulated Complex I plays a key role in maintaining redox balance
ROS and prevent oxidative damage, alongside other by transferring electrons to coenzyme Q (ubiquinone)
83
enzymatic (e.g., superoxide dismutase and catalase) or while simultaneously pumping protons across the inner
87
non-enzymatic (e.g., glutathione) antioxidant systems (e.g., mitochondrial membrane. The resulting proton gradient
superoxide dismutase 1/2). Taken together, mitochondrial is utilized by ATP synthase to drive ATP production,
dynamics and regulatory networks ensure mitochondrial as well as NADPH synthesis and metabolite transport.
function, health, and integrity, as well as the redox balance In LSCs, where glycolytic flexibility is limited, this
required to maintain functional, long-term HSCs. dependency on intact Complex I function highlights
a critical metabolic vulnerability. One study supports
3. Metabolic rewiring in LSCs the notion that CML LSCs are highly dependent on
mitochondrial oxidative metabolism for survival. This
25
Compared to the activation of quiescent HSCs, the finding confirms that mitochondrial activity and increased
oncogenic transformation of LSCs entails significant
metabolic reprogramming, allowing them to self-renew, TCA cycle catabolism in CML LSCs are not merely passive
survive in the BM niche, and resist therapeutic intervention characteristics but represent a critical energetic pathway
(Table 1; Figure 2). However, unlike quiescent HSCs, which that can be therapeutically targeted.
rely primarily on glycolysis for energy production, LSCs In addition to enhanced oxidative metabolism and TCA
exhibit enhanced mitochondrial respiration associated cycle activity observed in CML, LSCs in acute myeloid
with increased mitochondrial density. These changes are leukemia (AML) also rewire upstream metabolic inputs to

Volume 11 Issue 5 (2025) 55 doi: 10.36922/JCTR025320053