Page 60 - JCTR-11-5

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

glucose intake and providing the necessary metabolites for 2.2.1. Lipid metabolism
rapid expansion. 5,14,65 These include pyruvate, required for In addition to OXPHOS, mitochondria also play a major
mitochondrial OXPHOS, and other precursors required role in lipid metabolism, specifically FAO. FAO is a
60
5,22
66
for the biosynthesis of nucleotides, lipids, 60,67 proteins, metabolic process that breaks down fatty acids, supported
60
and carbohydrates. 52,60,68 by the presence of BM adipocytes, to generate the integral
In quiescent HSCs, mitochondrial OXPHOS is active metabolite acetyl-coenzyme A (CoA), required for the
but maintained at relatively low levels, potentially to limit tricarboxylic acid (TCA) cycle and downstream OXPHOS,
ROS generation, protect cells from oxidative damage, and as well as macromolecule biosynthesis. 22,73 In this process,
preserve their long-term self-renewal capacity. 1,4,5 This fatty acids undergo a series of reactions that repeatedly
suppression is maintained largely by the BM niche factors, shorten the fatty acid chain by two carbons while producing
cell dormancy, and several developmental pathways. acetyl-CoA, nicotinamide adenine dinucleotide (NADH),
Interestingly, quiescent HSC mitochondria are further and the reduced form of flavin adenine dinucleotide, which
repressed through the suppression of nuclear regulatory are needed for the TCA cycle and electron transport chain
factor 1 (NRF1) by sirtuin 7 (SIRT7). 1,24,69 NRF1 is (ETC), respectively, in addition to generating precursors
a transcription factor that regulates mitochondrial for macromolecule synthesis. In quiescent HSCs, FAO
biogenesis and function, enhancing OXPHOS and ROS is the primary form of lipid metabolism. Here, FAO is
accumulation. In contrast, SIRT7 acts as a metabolic sustained by the low levels of mitochondrial respiration
23
checkpoint that maintains HSC quiescence through the and is regulated by the peroxisome proliferator-activated
inhibition of NRF1. 70,71 Several studies suggest that this receptor-δ (PPARδ) transcription factor. PPARδ
5,22
interaction also suppresses the mitochondrial unfolded promotes the expression of genes regulating fatty acid
protein response and metabolic activation, thereby uptake, transportation, and oxidative catabolism to
enabling HSCs to maintain high levels of impaired preserve HSC longevity and self-renewal capacity while in
mitochondria while ensuring the rapid engagement the hypoxic BM niche. It then follows that loss of PPARδ
74
of OXPHOS upon HSC stimulation. 1,69,70 However, it results in a decline in HSCs with the ability to self-renew,
should be noted that quiescent HSC OXPHOS is not thereby supporting the role of FAO in HSC dormancy. 74
eliminated by these regulatory factors, as quiescent HSCs Upon activation, HSCs show a notable reconfiguration
remain dependent on minimal mitochondrial activity for in their lipid metabolic profile. Specifically, activated
survival. 1,4,5,9,10 HSCs are proposed to engage in a dynamic interplay

Several studies suggest that once activated, HSCs may between FAO and lipid macromolecule biosynthesis. 5,75,76
shift their metabolism to FAO and mitochondrial OXPHOS Sustained FAO assists in meeting the metabolic demands
to support proliferation, differentiation, and the energetic of activation but also contributes to differentiation
75
and biosynthetic demands sustained by the increased and fate determination through acetyl-CoA-dependent
76
concentration of mitochondria. 5,9,10,14 These demands histone modifications. Concurrently, lipid biosynthesis
include the expansion of mitochondrial mass, enhanced is upregulated in active HSCs to meet the increasing
respiratory capacity, and increased ATP production demand for building membranes required during rapid
in support of active cell cycle progression and lineage cell division. 77,78 Taken together, these findings further
specification. 5,9,10,14 An increase in OXPHOS coincides highlight the delicate balance of the metabolic profile
with elevated ROS production, which represents a major required to either maintain HSC dormancy or promote
step toward differentiation. ROS accumulation is known to differentiation.
drive HSCs out of quiescence by suppressing self-renewal
through the activation of p38 downstream of the mitogen- 2.3. Mitochondrial dynamics and ROS regulation
activated protein kinase signaling pathway. 1,5,14 A study Mitochondrial dynamics enable mitochondria to adapt
investigating the chemical uncoupling of mitochondrial to changing metabolic demands and regulate ROS levels
OXPHOS demonstrated that ex vivo HSCs exhibited lower required to exit quiescence. 5,9,10 The term “mitochondrial
mitochondrial mass and reduced mitochondrial membrane dynamics” refers to the continuous process of balancing
potential while displaying increased self-renewal potential mitochondrial fusion, fission, mitophagy, and biogenesis to
in cultures designed to induce differentiation. This maintain mitochondrial function, shape, and distribution
72
finding supports the role of limited mitochondrial activity within healthy cells. In HSCs, mitochondrial dynamics
79
as a key characteristic of HSC quiescence and heightened are critical for balancing fusion, fission, and mitophagy to
mitochondrial OXPHOS as a driver pushing HSCs out of preserve quiescence and self-renewal capacity, while also
quiescence. providing a structured means to enhance mitochondrial

Volume 11 Issue 5 (2025) 54 doi: 10.36922/JCTR025320053