Mitochondrial quality control in hematopoietic stem cells: mechanisms, implications, and therapeutic opportunities

Abstract

Mitochondrial quality control (MQC) is a critical mechanism for maintaining mitochondrial function and cellular metabolic homeostasis, playing an essential role in the self-renewal, differentiation, and long-term stability of hematopoietic stem cells (HSCs). Recent research highlights the central importance of MQC in HSC biology, particularly the roles of mitophagy, mitochondrial biogenesis, fission, fusion and mitochondrial transfer in regulating HSC function. Mitophagy ensures the removal of damaged mitochondria, maintaining low levels of reactive oxygen species (ROS) in HSCs, thereby preventing premature aging and functional decline. Concurrently, mitochondrial biogenesis adjusts key metabolic regulators such as mitochondrial transcription factor A (TFAM) and peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) to meet environmental demands, ensuring the metabolic needs of HSCs are met. Additionally, mitochondrial transfer, as an essential form of intercellular material exchange, facilitates the transfer of functional mitochondria from bone marrow stromal cells to HSCs, contributing to damage repair and metabolic support. Although existing studies have revealed the significance of MQC in maintaining HSC function, the precise molecular mechanisms and interactions among different regulatory pathways remain to be fully elucidated. Furthermore, the potential role of MQC dysfunction in hematopoietic disorders, including its involvement in disease progression and therapeutic resistance, is not yet fully understood. This review discusses the molecular mechanisms of MQC in HSCs, its functions under physiological and pathological conditions, and its potential therapeutic applications. By summarizing the current progress in this field, we aim to provide insights for further research and the development of innovative treatment strategies.

Introduction

Hematopoietic stem cells (HSCs) are essential for maintaining lifelong homeostasis of the hematopoietic system, characterized by their unique abilities of self-renewal and multipotent differentiation [1]. The function of HSCs is closely linked to their metabolic state and mitochondria is the key organelle for cellular metabolism and energy production in HSC. Aberrant mitochondrial function can impair the proliferation, differentiation, and regenerative capacity of HSCs, potentially leading to hematopoietic disorders [2]. Therefore, maintaining MQC is critical for preserving HSC functionality.

MQC is a dynamic and complex regulatory process encompassing mitophagy, biogenesis, fission, fusion and transfer mechanisms [3]. These processes collectively ensure mitochondrial integrity and stability. In HSCs, mitophagy removes damaged or aged mitochondria and plays a key role in sustaining a low metabolic state and mitigating oxidative stress [4]. Moreover, mitochondrial dynamics, including fission and fusion, have been implicated in the development and fate determination of HSCs [5]. Mitochondrial transfer, as a process of intercellular mitochondrial exchange, provides metabolic support to HSCs under stress and regulates their fate by influencing redox balance and signaling within the cellular microenvironment [6]. However, the specific mechanisms by which MQC regulates HSC function remain incompletely understood, particularly its dynamic changes under various physiological and pathological conditions.

In recent years, there has been significant progress in understanding the role of mitochondria in HSCs. Studies have shown that defects in mitophagy can lead to HSC aging and functional decline. Signaling pathways like PINK1-Parkin and FOXO3 are central for this process [7, 8]. Additionally, factors such as redox balance, mitochondrial membrane potential, and metabolic reprogramming also play critical roles [9]. However, many important questions are still unanswered. For instance, how do the molecular mechanisms of mitophagy specifically affect HSC function? How do different MQC processes work together to maintain homeostasis of HSC? Answering these questions will improve our understanding of HSC biology. It may also help identify new therapeutic targets for HSC-related disorders.

This review focuses on the roles of MQC in HSCs. It provides an overview of recent advancements in the field. Additionally, we discuss the molecular regulatory mechanisms of MQC and its impact on health and disease. Furthermore, we highlight several key areas for future research to offer insights into this rapidly evolving field.

Mitophagy in HSCs

Mechanism of mitophagy

The signaling pathways of mitophagy are primarily categorized into ubiquitin-dependent and non-ubiquitin-dependent pathways (Fig. 1), each relying on distinct molecules and mechanisms.

Fig. 1

The processes of mitophagy. Damaged mitochondria lose membrane potential (ΔΨm, MMP), triggering autophagosome formation and their encapsulation into mitophagosomes. These mitophagosomes subsequently fuse with lysosomes to form mature mitophagolysosomes, where lysosomal hydrolases degrade the damaged mitochondria, enabling nutrient recycling. Created in https://BioRender.com

The ubiquitin-dependent pathway is centered around the PINK1-Parkin signaling cascade [10]. PINK1 (PTEN-induced putative kinase 1) is a serine/threonine kinase that localizes to depolarized mitochondria. Under normal conditions, the cytoplasmic PINK1 precursor protein is imported into mitochondria via mitochondrial targeting sequences. Within the mitochondria, PINK1 undergoes proteolytic cleavage by proteases located in the mitochondrial matrix and inner membrane, after which it is released into the cytoplasm and degraded by the ubiquitin-proteasome system. However, when the mitochondrial membrane potential decreases, the translocation of PINK1 into the inner mitochondrial membrane is inhibited, causing its accumulation on the outer mitochondrial membrane (OMM). Here, PINK1 is activated through autophosphorylation and forms a dimer. Activated PINK1 recruits Parkin, an E3 ubiquitin ligase, from the cytoplasm to the OMM, enhancing its enzymatic activity. Parkin ubiquitinates mitochondrial OMM proteins, and the resulting ubiquitin chains are phosphorylated by PINK1 [11]. Phosphorylated ubiquitin-modified OMM proteins serve as “eat-me” signals recognized by autophagy adaptor proteins such as p62, OPTN (optineurin) and NDP52 (nuclear dot protein 52 kDa). These adaptor proteins facilitate the recruitment of autophagosomes, ultimately leading to the degradation of damaged mitochondria [12]. Moreover, studies indicate that PINK1 can directly recruit autophagy receptors OPTN and NDP52 to mitochondria via ubiquitin phosphorylation, bypassing Parkin to promote autophagy initiation [12, 13].

The ubiquitin-independent pathway is primarily mediated by mitophagy receptors such as NIX (Nip3-like protein X), BNIP3(BCL2/adenovirus E1B 19 kDa protein-interacting protein 3), and FUNDC1(FUN14 domain containing 1), which are localized to the mitochondrial membrane. These receptors possess a conserved microtubule-associated protein 1 light chain 3 LE(LC3)-interacting region (LIR) that directly binds to the autophagy-associated protein LC3, inducing selective mitochondrial degradation. For instance, NIX (also known as BNIP3L or BCL2/adenovirus E1B 19 kDa interacting protein 3-like) was initially recognized for mediating mitochondrial clearance during erythrocyte maturation. NIX proteins can directly interact with LC3 via their BH3 domain, thereby triggering the process of mitophagy [14]. BNIP3, particularly under hypoxic conditions, enhances mitophagy and protects cells from ROS-induced damage [15]. Similarly, FUNDC1, an OMM protein, mediates Parkin-independent mitophagy under hypoxic conditions by interacting with LC3. Another mitochondrial E3 ubiquitin ligase, MARCH5, also known as membrane-associated ring finger (C3HC4) 5, regulates FUNDC1-mediated mitophagy by ubiquitinating FUNDC1 under hypoxic conditions [16]. In addition to NIX, BNIP3, and FUNDC1, several other receptors have been identified to mediate ubiquitin-independent mitophagy by directly interacting with LC3 or other autophagy-related proteins. BCL2L13 (BCL2-like 13), a mammalian homolog of the yeast mitophagy receptor Atg32, functions as an OMM receptor that directly interacts with LC3 through its conserved LC3-LIR motif [17]. Another critical receptor, FKBP8 (FK506-binding protein 8), also functions in ubiquitin-independent mitophagy. FKBP8, an OMM protein, directly binds to LC3 through its LIR motif, acting as an essential mitophagy receptor in neural cells [18]. Unlike classical mitophagy receptors, FKBP8 contains a tetratricopeptide repeat (TPR) domain that facilitates its interaction with the autophagy machinery and contributes to mitochondrial clearance in a Parkin-independent manner. This pathway has been particularly implicated in neuronal homeostasis and survival, indicating its potential role in neurodegenerative disorders. PHB2 (Prohibitin 2) is another unique mitophagy receptor that resides in the inner mitochondrial membrane (IMM), distinguishing it from the previously discussed OMM receptors. PHB2 is normally embedded in the IMM but becomes exposed upon mitochondrial membrane depolarization or OMM rupture, allowing it to interact with LC3 and facilitate mitophagy [19]. PHB2 plays a crucial role in maintaining mitochondrial integrity and has been linked to mitochondrial quality control in aging and degenerative diseases. Additionally, CARD9 (Caspase recruitment domain-containing protein 9) has recently been recognized as an important mitophagy regulator. Unlike classical mitophagy receptors, CARD9 mediates mitochondrial clearance in response to cellular stress and plays a role in inflammatory signaling pathways. Studies suggest that CARD9 functions in a Parkin-independent manner to modulate mitochondrial homeostasis, although its exact molecular mechanisms require further investigation [20]. Together, these ubiquitin-independent mitophagy receptors operate through direct interactions with LC3 or other autophagy-related proteins, ensuring selective mitochondrial degradation and cellular homeostasis. Their roles in different physiological and pathological contexts, such as erythropoiesis, hypoxia adaptation, neuroprotection, and inflammation, highlight their importance as potential therapeutic targets in diseases associated with mitochondrial dysfunction.

Beyond these classical mechanisms, other pathways also contribute to mitochondrial clearance. For instance, lysosome-driven mitochondria-derived vesicles (MDVs) can rapidly respond to oxidative stress by selectively removing undepolarized yet damaged mitochondria [21]. Additionally, damaged mitochondria can be cleared through extracellular vesicles, facilitating their degradation in neighboring cells. This mechanism is especially relevant in neurons and cardiomyocytes [22, 23].

Mitophagy in embryonic HSCs

Embryonic HSCs originate in the aorto-gonado-mesonephric (AGM) region, where they undergo rapid proliferation in a high metabolic state to establish the hematopoietic system. Studies indicate that oxidative phosphorylation (OXPHOS) is the primary energy source for embryonic HSCs, with metabolic demands undergoing significant transitions during development. As HSCs migrate from the hyperoxic AGM region to the hypoxic environments of the fetal liver and bone marrow, their metabolism shifts progressively from OXPHOS to glycolysis. This metabolic adaptation is facilitated by the activation of mitophagy, which reduces mitochondrial load and enables HSCs to thrive in low-oxygen conditions while maintaining quiescence [24].

Developing embryonic HSCs requires mitophagy to eliminate maternally derived mitochondria and establish their metabolic profile. During this process, the HIF-1α signaling pathway supports adaptation to the hypoxic microenvironment by activating FundC1-mediated mitophagy [25]. Experimental evidence suggests that mitophagy protects neonatal HSCs from oxidative stress via p62-independent mechanisms, safeguarding long-term hematopoietic function [26]. Both mitophagy and autophagy rely on the formation of autophagosomes. They share similar molecular mechanisms, such as the recruitment of ATG proteins, the processing of LC3, the enclosure by double-membrane autophagosomes, and lysosome-mediated degradation. Deleting key autophagy-related genes, such as Atg5 and Atg7, disrupts mitochondrial homeostasis, leading to increased oxidative stress, loss of HSC quiescence, and severe hematopoietic defects, including bone marrow failure in adulthood [27]. Moreover, autophagy regulates the maturation of hematopoietic precursors during embryogenesis. Loss of Atg5 impairs autophagosome formation and mitochondrial activity, disrupting key hematopoietic processes [28]. Transcriptional regulation further links mitophagy to HSC maintenance. For instance, the transcription factor Nkx2-3 directly regulates ULK1, a critical mitophagy regulator, thereby ensuring HSC metabolic stability through the clearance of activated mitochondria [7]. In addition, replication stress in FANCD2-deficient fetal liver HSCs increases mitochondrial metabolism and mitophagy, suggesting the unique metabolic activity in fetal HSCs compared to adult HSCs [29]. These fetal-specific characteristics include elevated OXPHOS and tricarboxylic acid cycle (TCA) activity.

The transparency of zebrafish embryos makes them highly useful for studying hematopoietic cell development and the role of mitophagy in HSC [30]. In zebrafish models, Bnip3lb-driven mitophagy regulates ROS levels and prevents apoptosis, promoting the expansion of the embryonic HSC pool. This process is essential for maintaining the pluripotency and function of hematopoietic progenitor cells. In human models, activation of mitophagy has been shown to enhance the hematopoietic capacity of progenitor cells derived from induced pluripotent stem cells (iPSCs) [31]. Nicotinamide riboside (NR), a precursor of nicotinamide adenine dinucleotide (NAD+), has been shown to enhance mitophagy by activating SIRT1 pathways [32]. This process is essential for clearing dysfunctional mitochondria and maintaining mitochondrial integrity, which is critical for preserving the physiological function and self-renewal capacity of HSCs. Notably, interventions such as NR activation significantly improve HSC production in zebrafish embryos and enhance the longevity and functional capacity of human HSCs and progenitor cells in vivo [33]. These findings highlight the vital role of mitophagy in embryonic HSC development. Dysregulated mitophagy leads to impaired HSC maturation and migration, as shown by increased oxidative stress and disrupted hematopoietic function. These studies provided a basis for creating therapeutic strategies to improve HSC functionality by targeting mitophagy.

Mitophagy in adult HSCs

Adult HSCs are uniquely characterized by low metabolic activity and depend on stringent MQC to avoid ROS accumulation and mitochondrial dysfunction [4]. Mitophagy ensures long-term stemness and self-renewal by removing damaged mitochondria, maintaining metabolic homeostasis, and fulfilling energy requirements. Studies using mouse models have shown that deleting mitophagy-related genes, like PINK1 or Parkin, causes mitochondrial dysfunction, higher ROS levels, and accelerated HSC depletion [8, 9]. ROS accumulation damages HSCs DNA and proteins, impairing self-renewal capacity. Additionally, mitophagy regulates the expression of critical mitochondrial proteins like Sirt3, a deacetylase essential for mitochondrial function and antioxidant defense [34]. Murakami et al. demonstrated that OGT (O-GlcNAc transferase) regulates mitophagy to maintain HSC homeostasis and function. OGT deficiency results in increased ROS levels, mitochondrial dysfunction, and apoptosis in HSCs, alongside reduced expression of crucial mitophagy regulators, including PINK1 and BNIP3. Overexpressing PINK1 restored mitophagy and alleviated the phenotypes caused by OGT deficiency [8]. An increasing number of studies have uncovered additional upstream regulators of mitophagy in HSCs, summarized in Table 1.

Table 1 Genes targeting mitochondrial quality control to regulate HSC function

HSCs are predominantly quiescent but occasionally divide and self-renew to maintain the stem cell pool and continuously replenish blood cells. HSC division occurs in two primary forms: symmetric and asymmetric division. Symmetric self-renewal occurs when HSCs divide to produce two daughter cells that retain full stem cell properties, expanding the stem cell pool. This mode is commonly observed during embryonic development or in response to severe tissue damage, allowing the stem cell population to replenish rapidly. In contrast, symmetric differentiation involves HSCs dividing to generate two differentiated progenitor cells, which lose their stem cell identity and contribute to producing specialized cells required for hematopoiesis. This typically occurs during periods of high hematopoietic demand, such as infection or recovery from blood loss. In asymmetric division, one daughter cell retains stem cell identity, maintaining the stem cell pool, while the other differentiates into a progenitor cell, contributing to hematopoietic homeostasis [59]. Tie2-expressing HSCs (Tie2 + HSCs) are a subpopulation characterized by their quiescent nature, high self-renewal capacity, and resistance to apoptosis. These cells are critical for long-term hematopoiesis, and their survival depends on tightly regulated mitophagy to remove damaged mitochondria and prevent oxidative stress-induced differentiation. Disruptions in mitophagy can compromise the stemness of Tie2 + HSCs, leading to functional exhaustion. A study by Ito et al. demonstrated that mitochondrial clearance is essential for the self-renewal of a purified Tie2 + HSC population. They showed that mitophagy, particularly in Tie2-expressing quiescent HSCs, is crucial for maintaining stemness and preventing differentiation. This process is mediated by the PINK1-Parkin dependent pathway, which selectively degrades dysfunctional mitochondria to maintain metabolic homeostasis in HSCs. The loss of mitophagy results in increased mitochondrial mass, elevated ROS levels, and HSC exhaustion, ultimately impairing long-term hematopoiesis [49]. Their previous study also indicated that the promyelocytic leukemia protein (PML)/peroxisome proliferator-activating receptor type δ (PPARδ) axis promotes asymmetric division by upregulating PINK1-Parkin mediated mitophagy [60].

During HSC differentiation, metabolic reprogramming requires precise mitochondrial regulation. By regulating mitochondrial number and quality, mitophagy facilitates the shift from glycolysis to OXPHOS, ensuring the energy needs of different hematopoietic cell types are met (Fig. 2) [61]. Selective mitochondrial clearance during differentiation minimizes ROS accumulation, preventing oxidative stress from disrupting the differentiation process. When the PINK1-Parkin pathway is impaired, HSC maintenance is significantly inhibited, particularly under stress-induced hematopoietic conditions [62]. Dysregulation of mitophagy can also lead to imbalances in HSC differentiation. For instance, FUNDC1-mediated mitophagy regulates HSC differentiation under hypoxic conditions, and dysfunction in this pathway may result in asymmetric differentiation toward myeloid or gonadal hematopoiesis [63, 64].

Fig. 2

Mitophagy Maintains Hematopoietic Stem Cell Self-Renewal and Influences Differentiation Potential. HSCs reside in a hypoxic environment with low levels of growth factors. HSCs rely on glycolysis as their primary energy source in their quiescent and self-renewing states. This metabolic state promotes the activation of transcription factors such as PPARδ, ATAD3A, TGFβ1 and FOXO3 and reduces ROS production, protecting HSCs from oxidative damage and preserving their long-term stemness. HSC differentiation is associated with increased ROS levels and activation of the mammalian target of rapamycin (mTOR). As HSCs differentiate into downstream progenitors, their metabolism shifts from glycolysis to mitochondrial oxidative phosphorylation (OXPHOS) to meet higher energy demands. HPC, Hematopoietic Progenitor Cell; FA, fatty acid; ADP, adenosine diphosphate; ATP, adenosine triphosphate; AMP, Adenosine Monophosphate; TCA, tricarboxylic acid cycle. Created in https://BioRender.com

The cell cycle dynamics of HSCs are closely linked to their ability to self-renew and differentiate. Quiescent HSCs rely on mitophagy to sustain a low metabolic state and ensure mitochondrial stability. This process is essential for maintaining their long-term functionality. In contrast, when HSCs enter the active cell cycle, they require elevated metabolic activity to support proliferation [65]. Mitophagy regulates explicitly the transition of HSCs from the G0 to the G1 phase by modulating the expression of cell cycle-related proteins such as Cyclin D and CDK4/6 [66]. Without functional mitophagy, HSCs may accumulate damaged mitochondria during cell cycle arrest, leading to increased apoptosis or reduced proliferative capacity. This phenomenon is particularly pronounced under stress-induced hematopoiesis, such as during bone marrow transplantation or inflammatory responses, where inhibition of mitophagy significantly impairs HSC expansion [67]. Moreover, mitophagy ensures smooth cell cycle progression by maintaining mitochondrial membrane potential and mitigating ROS accumulation. Activation of the PINK1-Parkin pathway regulates cell cycle progression, enhances long-term proliferation, and preserves the stemness of HSCs [64]. These findings indicated the critical role of mitophagy in coordinating the HSC cell cycle and highlighted its importance for sustaining HSC function in both physiological and stress-induced conditions.

HSC transplantation is an important treatment for blood disorders like leukemia and aplastic anemia. However, HSCs are highly susceptible to oxidative and metabolic stress during in vitro expansion and transplantation, often resulting in functional decline and graft failure. Recent studies suggest that modulating mitophagy can greatly improve HSC function and graft success rate [68]. The long-term function of HSCs relies on maintaining a quiescent state, which mitophagy facilitates by removing damaged mitochondria and reducing ROS accumulation. Small-molecule drugs that enhance mitophagy, such as those activating PINK1-Parkin signaling, can protect HSCs from the adverse effects of metabolic stress, thereby improving their survival and functional recovery post-transplantation [69]. A major challenge in expanding HSCs in vitro is to maintain their stemness. Modulating mitophagy-related molecules, such as BNIP3 or FUNDC1, can inhibit premature entry of HSCs into the cell cycle, thereby better maintaining their self-renewal capacity during expansion. This approach holds great potential for producing functional HSC donors for clinical applications.

Mitophagy in aged HSCs

At the cellular level, aged HSCs are characterized by increased oxidative stress, epigenetic dysregulation, impaired DNA repair, and metabolic shifts toward OXPHOS. These changes reduced their regenerative ability and caused skewed differentiation within the bone marrow. Externally, the aging bone marrow microenvironment impaired HSC dysfunction by increasing inflammation and metabolic stress. This disrupts the balance between quiescence and activation of HSCs [70]. Interestingly, while the number of HSCs increases with age, their functionality, self-renewal ability, homing efficiency, and lymphoid differentiation potential decline significantly during aging [71]. Elucidating the interplay between intrinsic factors, such as ROS-induced damage and metabolic dysregulation, and extrinsic niche contributions offers a foundation for developing interventions to rejuvenate aging HSCs, restore hematopoietic function, and mitigate immune senescence in older people.

Mitochondrial dysfunction represents a hallmark of aging in HSCs, manifested as increased OXPHOS activity and excessive ROS production, which accelerate metabolic stress and cellular damage [72]. Selective autophagy of damaged mitochondria is critical for maintaining HSC functionality and metabolic homeostasis during aging. Functional decline in aged HSCs is a major contributor to conditions such as senile anemia and hematopoietic disorders. Notably, interventions targeting mitophagy have shown potential in reversing age-associated phenotypes. For instance, urolithin A has been demonstrated to restore mitochondrial homeostasis and immune function, while autophagy activation upregulates Sirt3, reduces oxidative stress, and preserves HSC regenerative capacity [40, 73]. Furthermore, a subset of aged HSCs with high autophagy activity maintains low metabolic states and strong functionality, indicating the therapeutic potential of enhancing mitochondrial turnover. Strategies such as mitophagy inducers or mitochondrial antioxidants, including Mito-Q, have shown promise in alleviating HSC aging, restoring hematopoietic function, and improving immune resilience in elderly individuals [74]. Activation of pathways such as AMPK and Sirt3 has been shown to enhance mitophagy, thereby reducing ROS accumulation and metabolic stress, ultimately improving the self-renewal and differentiation potential of aged HSCs [75]. These interventions not only ameliorate senile anemia but may also delay the onset of other hematopoietic decline-associated conditions. Anti-aging therapies targeting mitophagy, including small molecule activators like nicotinamide riboside or resveratrol, have demonstrated efficacy in delaying HSC aging and represent promising therapeutic avenues for older patients [33, 76].

Aging HSCs exhibit diminished functionality due to intrinsic and extrinsic factors, culminating in impaired hematopoiesis and increased susceptibility to age-associated diseases such as anemia, myelodysplastic syndrome (MDS), and acute myeloid leukemia (AML). Mitophagy is critical in erythropoiesis and other hematopoietic functions, particularly during erythrocyte maturation, by removing excess mitochondria and organelles. This process is essential for normal erythrocyte development and functional maintenance [77]. Deletion of autophagy-related genes, such as ATG4A, has been shown to impair mitochondrial clearance in erythrocytes, leading to ineffective erythropoiesis and anemia [78]. During erythrocyte maturation, mitophagy receptors, including BNIP3 and NIX, specifically target mitochondria for removal, ensuring proper morphology and function of erythrocytes. Disruption of this process causes anemia and may trigger broader hematopoietic dysfunction linked to metabolic dysregulation [79]. Mortensen et al. demonstrated that mitophagy selectively removes mitochondria, rather than other organelles, during erythropoiesis. Mice deficient in the autophagy gene Atg7 exhibited impaired mitochondrial clearance, altered mitochondrial membrane potential, and severe anemia [80]. Similarly, Geng et al. found that the mitophagy receptor FUNDC1 plays a crucial role in stress-induced erythropoietin (EPO) production by maintaining MQC. Deficiency in FUNDC1 led to damaged mitochondria, elevated ROS levels, and increased inflammatory responses, inhibiting renal erythropoietin-producing cells (REPs) and triggering renal anemia [81].

Aplastic anemia (AA) and MDS are strongly linked to aberrant mitophagy. For instance, Cao et al. reported that ginsenoside Rg1 improved HSC function in an AA mouse model by inhibiting Bax mitochondrial translocation and apoptosis-related pathways, thereby reducing ROS levels, increasing mitochondrial abundance, and enhancing the Bcl-2/Bax ratio. Rg1 significantly lowered the expression of mitochondrial apoptosis-associated proteins, increased peripheral blood and LSK cell counts, restored mitochondrial function, and promoted hematopoietic recovery [82]. In MDS, mitochondrial dysfunction is frequently accompanied by impaired mitophagy pathways, leading to defective differentiation of hematopoietic progenitor cells and metabolic imbalance. Nix-mediated mitophagy impairment in nucleated red blood cells (NRBCs) within MDS bone marrow has been associated with mitochondrial damage, elevated ROS levels, apoptosis, and ineffective erythropoiesis [83]. Additionally, Stergiou et al. identified that activation of the HIF-1α/REDD1 pathway in MDS bone marrow cells was linked to increased autophagy and mitophagy. This metabolic dysregulation was characterized by enhanced glycolysis, OXPHOS defects, glutamine metabolism abnormalities, and decreased mitochondrial mass and membrane potential—HIF-1α-driven metabolic disruption correlated with elevated 2-hydroxyglutarate levels and epigenetic dysregulation [84].

HSC aging is a key contributor to hematopoietic dysfunction and transplant failure, with MQC playing a central role in maintaining stem cell integrity. Aged HSCs exhibit increased mitochondrial mass, impaired mitophagy, and excessive ROS accumulation, leading to metabolic stress, DNA damage, and diminished regenerative potential [72]. These intrinsic defects not only compromise the ability of aged HSCs to efficiently engraft post-transplantation but also contribute to skewed myeloid-biased differentiation and immune dysfunction. Mitochondrial dysfunction in aged HSCs results in a decline in OXPHOS efficiency, further impairing self-renewal and hematopoietic reconstitution following transplantation [4]. Additionally, a pro-inflammatory bone marrow microenvironment exacerbates mitochondrial stress, promoting apoptosis and reducing the survival of transplanted HSCs. Enhancing MQC through pharmacological activation of mitophagy, mitochondrial biogenesis, and antioxidants has emerged as a promising strategy to rejuvenate aged HSCs and improve transplantation outcomes [85]. For instance, nicotinamide riboside and mitochondrial-targeted antioxidants have been shown to enhance mitochondrial clearance, reduce ROS burden, and improve engraftment efficiency of aged HSCs [33, 86]. Furthermore, studies have indicated that AMPK and SIRT3 activation enhances mitochondrial turnover, restoring metabolic flexibility and self-renewal capacity in aging HSCs, which may mitigate transplant failure risks [40, 87]. Addressing MQC dysregulation in aged HSCs thus represents a critical therapeutic avenue for enhancing hematopoietic recovery post-transplantation, improving graft durability, and reducing immune-related complications in elderly patients receiving stem cell therapy.

Mitophagy in leukemia stem cells

Leukemia stem cells (LSCs) are generally the result of genetic mutations in normal HSCs or progenitor cells. These mutations provided them abnormal self-renewal capacity and a proliferative advantage while impairing their normal differentiation functions. Normal HSCs maintain the stability of the hematopoietic system, whereas LSCs disrupt normal hematopoiesis by uncontrolled proliferation and aberrant differentiation, leading to the formation of leukemic cell populations [88]. Mitophagy is crucial in the development and progression of leukemia, particularly in the maintenance of LSCs. Enhanced mitophagy enables LSCs to achieve metabolic homeostasis and develop drug resistance. By removing damaged mitochondria and preventing the accumulation of ROS, mitophagy supports the cellular quiescent state and energy metabolism homeostasis—critical mechanisms for maintaining LSCs stemness and driving disease progression [89]. The persistence and drug resistance of LSCs are key contributors to leukemia treatment failure. LSCs rely on mitophagy to maintain their metabolic dominance and stemness, making mitophagy a promising target for therapeutic intervention (Fig. 3). Activation of the AMPK/FIS1-mediated mitophagy pathway enables LSCs to preserve their stemness, while inhibition of AMPK or FIS1 disrupts mitophagy, leading to a loss of LSC function and promoting myeloid differentiation [45].

Fig. 3

Mitochondrial quality control and hematopoietic diseases. HSCT: hematopoietic stem cell transplantation. Created in https://BioRender.com

In AML, mitophagy regulated through p62 is essential for the survival of leukemia-initiating cells (LICs). Inhibition of p62 selectively targets LICs by blocking mitophagy while sparing normal HSCs [46]. In AML patients with FLT3-ITD mutations, LSCs exhibit elevated mitophagy levels, which facilitate the clearance of excess mitochondria and reduction of ROS levels, preserving the quiescent state of LSCs [90].

When autophagy is inhibited, mitochondria is accumulated in LSCs, resulting in increased OXPHOS, metabolic imbalances, and differentiation. This ultimately reduces their regenerative capacity [90]. Moreover, autophagy inhibition activates the p53 pathway and enhances apoptosis, presenting new therapeutic possibilities for AML by targeting autophagy [91]. Mitophagy inhibitors, such as Bafilomycin A1 (Baf A1), significantly enhance AML cell death by reducing mitochondrial respiration, stabilizing PINK1-induced mitochondrial damage, and blocking mitophagy. In vivo studies show that combining Baf A1 with Ara-C effectively reduces AML tumor burden [92]. In AML, abnormally active mitophagy caused by FLT3-ITD mutations enables LSCs to resist chemotherapy and oxidative stress [93]. Drugs that inhibit mitophagy, such as chloroquine (CQ) or specific PINK1 inhibitors, disrupt LSC metabolic homeostasis and induce differentiation or apoptosis, enhancing the efficacy of chemotherapeutic agents [94]. Targeting non-ubiquitin-dependent mitophagy pathways, such as those mediated by FUNDC1 or BNIP3, has also been suggested as a potential strategy for combating LSC resistance while minimizing side effects on normal HSCs [95, 96]. Dany et al. demonstrated that inhibiting FLT3-ITD induces ceramide-dependent mitophagy and cell death. They proposed that LCL-461, a mitochondria-targeted ceramide analog, could overcome AML resistance by restoring ceramide function, suggesting mitophagy as a novel therapeutic target in AML [97]. The dependence of AML cells on mitophagy increases under hypoxic conditions, and autophagy inhibitors such as Lys05 significantly enhance the elimination of AML cells and LSCs by blocking mitophagy. This underscores the potential for developing lysosome-based autophagy inhibitors for AML treatment [98]. Glytsou et al. identified a new mitophagy-related therapeutic target in AML using genome-wide CRISPR/Cas9 screens. They found that overexpression of the mitophagy regulator MFN2 drives AML resistance to BH3 mimetics while targeting MFN2-enhanced BH3 mimic-induced apoptosis through genetic and pharmacological means [99]. Similarly, Meyer et al. used pairwise multiplexed CRISPR screening to resolve the functional network of mitophagy receptors in AML. They identified OPTN as the only non-redundant mitophagy receptor. OPTN regulates AML cell proliferation, and its deletion impairs mitochondrial function, prolonging survival in AML mouse models. This positions OPTN as a promising target for AML therapy [100]. High autophagy-mitophagy flux (e.g., elevated expression of MAP1LC3B and BNIP3) correlates with low glycolysis rates (e.g., reduced expression of HK2, PFKM and PKM) in AML patients, predicting better clinical prognosis. Transcriptomic analyses revealed that this metabolic profile is associated with enhanced anti-tumor responses and cell death [100]. These findings suggest combining autophagy inducers with glucose-limiting agents may represent a novel strategy for improving AML treatment outcomes.

In acute lymphoblastic leukemia (ALL), ALL cells leverage mitophagy to manage metabolic and drug-induced stress by eliminating damaged mitochondria, thus maintaining metabolic homeostasis and redox balance [101]. Targeting mitophagy has become a promising strategy to enhance the sensitivity of ALL cells to chemotherapy. Inhibiting mitophagy disrupts the protective mechanisms of ALL cells, leading to increased apoptosis and decreased proliferation. Jing et al. demonstrated that a combination of the antimalarial drug Quinacrine (QC) and the HDAC (Histone deacetylases) inhibitor vorinostat significantly increased apoptosis in T-cell acute lymphoblastic leukemia (T-ALL) cells by elevating ROS levels and suppressing mitophagy [102].

Aberrant mitophagy regulation has also been observed in chronic myeloid leukemia (CML). BCR-ABL1(Breakpoint Cluster Region-Abelson 1)-positive cells enhance mitophagy via upregulation of the PINK1-Parkin pathway in response to stress, contributing to drug resistance and disease progression in CML [103]. Ianniciello et al. found that mitophagy is crucial for reactivating proliferation in CML CD34⁺ cells after hypoxia-induced quiescence. In contrast, normal CD34⁺ cells do not rely on mitophagy for survival [104]. Targeting mitophagy represents a novel strategy to disrupt the survival and function of LSCs, offering potential therapeutic opportunities for anti-leukemia treatments. Beyond hematopoietic malignancies, mitochondrial dysfunction and mitophagy dysregulation have been implicated in a wide range of diseases, including neurodegenerative disorders, metabolic syndromes, and solid tumors [105, 106]. Recent studies suggest that defective mitophagy contributes to tumor progression by allowing cancer cells to escape apoptosis and adapt to metabolic stress, making mitophagy a potential therapeutic target in oncology [107]. Moreover, impaired mitophagy in metabolic diseases can lead to mitochondrial accumulation and increased oxidative damage, exacerbating disease pathology [108]. Chronic psychological stress also plays a crucial role in activating HSC proliferation and mobilization from the bone marrow into the peripheral blood, thereby contributing to atherosclerosis and cardiovascular diseases. This process is primarily driven by increased sympathetic nervous system activity, leading to elevated norepinephrine signaling, which in turn stimulates HSC egress [109]. Additionally, stress-induced mitochondrial dysfunction and increased ROS levels in HSCs may accelerate their differentiation into myeloid-biased progenitors, further promoting systemic inflammation and atherosclerotic progression [110, 111]. Understanding the MQC mechanisms involved in this response may offer potential therapeutic interventions for stress-related cardiovascular conditions. These findings underscore the need for further research into how modulating mitophagy could provide novel treatment strategies for various diseases beyond hematopoiesis.

Mitochondrial biogenesis in HSCs

Mechanism of mitochondrial biogenesis

Mitochondrial biogenesis is the process of increasing the number and functionality of mitochondria. It is regulated by a complex network of molecular signaling pathways and protein interactions. This process is regulated by key transcription factors, including PGC-1α, nuclear respiratory factor 1 (NRF1), and nuclear respiratory factor 2 (NRF2) (Fig. 4). PGC-1α interacts with NRF1 and NRF2 to activate mitochondrial-related gene expression, thereby promoting mitochondrial DNA replication, transcription, and the assembly of electron transport chain complexes [35, 112].

Fig. 4

The key molecular mechanisms governing mitochondrial dynamics, biogenesis, and mitophagy. Mitochondrial biogenesis is regulated by the AMPK-PGC-1α-NRF1/2-TFAM signaling pathway, which promotes the formation of new mitochondria. Mitochondrial dynamics involve a balance between fission and fusion processes. Fission, mediated by Drp1, facilitates mitochondrial division, which is crucial for quality control and cellular energy demands. Fusion, regulated by MFN1, MFN2, and OPA1, supports mitochondrial network integrity and functional maintenance. Mitophagy, a selective form of autophagy, is triggered by a reduction in mitochondrial membrane potential (ΔΨm↓) and involves key regulators such as PINK1, Parkin, NDP52, OPTN, and NIX, leading to lysosomal degradation of damaged mitochondria. The mTOR pathway negatively regulates both fission and mitophagy, thereby influencing mitochondrial turnover and homeostasis. Created in https://BioRender.com

Within mitochondrial biogenesis, TFAM regulates the replication and transcription of mitochondrial DNA, ensuring its integrity [85]. Additionally, mitochondrial biogenesis is influenced by the activation of AMPK and the mTORC1. AMPK activates PGC-1α to enhance energy metabolism, while mTORC1 contributes by modulating nutrient signals [113, 114]. Oxidative stress and metabolic demands influence mitochondrial biogenesis. Under hypoxic conditions, HIF-1α supports glycolysis and reduces excessive mitochondrial OXPHOS, which regulates the mitochondrial metabolic state in HSCs [85].

The impact of mitochondrial biogenesis on HSCs function

Mitochondrial biogenesis is crucial for the function of HSCs. HSCs predominantly rely on glycolysis to maintain a low metabolic state, reducing the production of ROS and protecting their stemness and self-renewal capacity. However, when HSCs transition from quiescence to proliferation and differentiation, mitochondrial biogenesis is significantly activated to meet the energy and metabolic demands [114]. During this process, the expression of PGC-1α is essential for stress-induced hematopoiesis. For instance, under mild hypoxic conditions, PGC-1α promotes mitochondrial biogenesis and enhances the clonogenic potential of HSCs. Loss of PGC-1α severely impairs the long-term regenerative potential of HSCs and disrupts their function under stress [112]. Additionally, studies have shown that the loss of mitochondrial phosphatase PTP localized to the Mitochondrion 1 (PTPMT1) or key components of the electron transport chain complex III, reiske iron-sulfur center protein (RISP), leads to mitochondrial dysfunction in HSCs, thereby impairing their differentiation and regenerative capacity [115]. The dynamic regulation of mitochondria also significantly influences HSC function. The balance between fission and fusion ensures mitochondrial quality and function, protecting HSCs from damage. Excessive mitochondrial fission can lead to ROS accumulation and HSC exhaustion, while insufficient fusion disrupts differentiation [116].

The role of mitochondrial biogenesis in hematopoietic diseases

Abnormal regulation of mitochondrial biogenesis is closely associated with various hematopoietic diseases. In cases of mitochondrial dysfunction, elevated ROS levels cause DNA damage, leading to HSC exhaustion or abnormal differentiation, which is particularly evident in bone marrow failure syndromes and leukemia [115]. Leukemic stem cells often exhibit higher mitochondrial biogenesis and OXPHOS activity, making them more susceptible to therapies targeting mitochondrial metabolism. Moreover, mitochondrial biogenesis is linked to HSC aging. The accumulation of mitochondrial DNA mutations in HSCs accelerates functional decline and leads to premature aging phenotypes [35]. Mitochondrial biogenesis plays a central role in maintaining HSC self-renewal, differentiation, and stress responses. A deeper understanding of the regulatory mechanisms of mitochondrial biogenesis and its relationship with HSC-related diseases will not only provide insights into the metabolic regulation of HSCs but also offer new strategies for improving HSC transplantation and treating hematological disorders.

Mitochondrial dynamics in HSCs

Mechanism of mitochondrial dynamics

Mitochondrial dynamics refers to the continuous and coordinated processes of mitochondrial fission and fusion that regulate the morphology, size, distribution, and function of mitochondria within cells. This dynamic equilibrium is governed by specific proteins: fusion is mediated by Mitofusin 1/2 (MFN1/2) and OPA1, which facilitate outer and inner membrane fusion, respectively, while fission is driven primarily by dynamin-related protein 1 (Drp1) and FIS1. During fusion, mitochondria join to form more extensive, interconnected networks that optimize energy production and resilience against stress. Conversely, fission segregates damaged mitochondria, allowing their removal via mitophagy [5]. This quality control system maintains functional mitochondrial populations. It balances energy production and cellular health under different physiological and stress conditions. These dynamics are crucial for metabolism, signaling, and survival across various cell types, including HSCs [73].

The impact of mitochondrial dynamics on HSCs function

Long-term HSCs reside in a metabolically quiescent state within hypoxic bone marrow niches. They primarily rely on glycolysis for energy, which helps reduce ROS production. This metabolic state preserves HSCs from oxidative stress and supports their long-term self-renewal capacity. However, as HSCs activate for proliferation or differentiation, a metabolic shift occurs, with an increase in mitochondrial OXPHOS and mitochondrial activity. Mitochondrial dynamics play a critical role in orchestrating these transitions [117]. Mitochondrial fission segregates damaged components, preventing ROS accumulation that could impair HSCs quiescence and self-renewal. Drp1-mediated fission is essential for maintaining HSC function, its deficiency results in mitochondrial aggregation, disrupted HSC homeostasis, and diminished regenerative potential [4].

During HSC activation, mitochondrial fusion forms a connected network, enhancing ATP production and stress resilience. This network supports the energy-intensive demands of cell proliferation and differentiation, preserving HSC functionality during lineage commitment [5]. Mitochondrial dynamics also influence HSC asymmetric division. Damaged mitochondria are preferentially allocated to differentiating progeny, while healthy mitochondria remain in the stem cell compartment. This asymmetric distribution ensures the maintenance of stem cell integrity and prevents the accumulation of dysfunctional organelles within the HSC pool [118].

The role of mitochondrial dynamics in hematopoietic diseases

Aging HSCs exhibit reduced self-renewal and altered differentiation potential, skewing toward myeloid lineages. Mitochondrial dynamics are deeply implicated in these age-related changes. Dysregulation of mitochondrial fission and fusion contributes to the accumulation of dysfunctional mitochondria, increased ROS production, and impaired HSC function [72]. In aged HSCs, decreased mitochondrial fission and reduced mitophagy lead to an accumulation of damaged mitochondria, which generates excess ROS. Oxidative stress leads to genomic instability, senescence, and reduced regenerative capacity. In addition, aged HSCs show higher mitochondrial membrane potential and increased OXPHOS activity, which are associated with their myeloid-biased differentiation [72].

In AML, leukemic stem cells exhibit altered mitochondrial dynamics that differ from normal HSCs. LSCs rely heavily on functional mitochondrial networks to sustain their high metabolic demands. Disruption of these dynamics, such as inhibiting BCL-2 or targeting Drp1, selectively impairs LSC survival while sparing normal HSCs. This differential dependence offers a promising therapeutic avenue for selectively targeting malignant cells [119]. Targeting mitochondrial dynamics could mitigate age-related HSC decline and improve therapeutic outcomes. Enhancing mitophagy to remove dysfunctional mitochondria or restoring the balance between fission and fusion may preserve HSC function. Pharmacological interventions targeting MQC mechanisms, such as nicotinamide or autophagy enhancers, are under investigation for their potential to rejuvenate aged HSCs and suppress leukemic progression [119]. Mitochondrial dynamics represent a cornerstone of HSC biology, orchestrating MQC through fission and fusion. These processes are essential for maintaining HSCs’ quiescence, self-renewal, and lineage commitment. Disrupted mitochondrial dynamics lead to HSC aging, impaired function, and hematologic malignancies. Gaining a deeper understanding of mitochondrial dynamics in HSCs could provide valuable insights for developing novel therapeutic strategies to combat aging-related dysfunction and treat hematologic disorders.

Mitochondrial transfer in HSCs

Mitochondrial transfer is an emerging field in HSC research, and related studies are still in the primary exploration stage. It is a pivotal mechanism in the bone marrow (BM) microenvironment that influences HSCs metabolism, function, and overall hematopoiesis. This process involves the transfer of functional mitochondria from donor cells, such as bone marrow stromal cells (BMSCs), to recipient HSCs or hematopoietic progenitor cells (HPCs). The intercellular exchange of mitochondria occurs through specialized structures and pathways that help maintain HSC homeostasis and adapt to physiological or pathological stress. The following sections explore the process and mechanisms of mitochondrial transfer, its effects on HSC function, and its implications in hematopoietic diseases.

Mechanism of mitochondrial transfer

Mitochondrial transfer between cells is mediated by direct physical connections, such as tunneling nanotubes (TNTs) and gap junctions, or through extracellular vesicles (EVs) (Fig. 5). These pathways enable the exchange of mitochondria and other cellular components, ensuring the functional integrity of recipient cells. TNTs are actin-based structures that establish direct cytoplasmic continuity between donor and recipient cells, allowing the transfer of mitochondria, organelles, and macromolecules. TNT-mediated mitochondrial transfer has been extensively observed in the BM niche, particularly between BMSCs and HSCs [120]. ROS is key in inducing TNT formation. For instance, NOX2-generated ROS from recipient cells can stimulate mitochondrial transfer from BMSCs, as observed in AML. TNT-mediated transfer also helps leukemic cells withstand oxidative stress and chemotherapeutic challenges [121]. Connexin-43 (Cx43) gap junctions are another key mechanism for mitochondrial transfer. These intercellular channels allow cytoplasmic continuity, facilitating the exchange of ions, small molecules, and organelles. Gap junction-mediated transfer ensures the delivery of functional mitochondria to HSCs, supporting their bioenergetic needs during hematopoietic stress. The bi-directional exchange of mitochondria via gap junctions also aids in the repair of damaged BMSCs, indicating the dynamic metabolic coupling within the BM niche [6]. EVs, including exosomes and microvesicles, provide an alternative pathway for mitochondrial transfer. These vesicles transport mitochondrial fragments or whole mitochondria, contributing to cellular repair and immune modulation [115]. Although EV-mediated transfer is less prominent than TNTs and gap junctions, it is increasingly recognized for its involvement in niche remodeling and stress adaptation in hematopoiesis.

Fig. 5

Mechanisms of Mitochondrial Transfer Between Cells. (A) Tunneling nanotubes (TNTs) facilitate direct mitochondrial transport between cells via thin cytoplasmic bridges. (B) Extracellular vesicles (EVs) enable mitochondria to be encapsulated and transported to recipient cells. (C) Extrusion, where mitochondria are actively expelled from the donor cell and taken up by the recipient. (D) Gap junction channels (GJCs) allow the direct passage of mitochondria or mitochondrial components between adjacent cells. Created in https://BioRender.com

The impact of mitochondrial transfer on HSCs function

Mitochondrial transfer profoundly influences the metabolism, maintenance, and function of HSCs, particularly during hematopoietic stress or increased demand. Under normal conditions, HSCs rely predominantly on glycolysis to maintain their quiescent state. However, during periods of stress or activation, mitochondrial transfer enables HSCs to shift their metabolism toward OXPHOS [122]. This shift supports increased ATP production and bioenergetic capacity, which are essential for HSC activation, proliferation, and differentiation. The ability of BMSCs to provide functional mitochondria to HSCs ensures their rapid response to hematopoietic emergencies, such as infections or myeloablation [123]. Mitochondrial transfer also contributes to the quality control of HSCs by replacing damaged mitochondria with healthy ones from donor cells. This process prevents the accumulation of dysfunctional organelles, mitigating oxidative damage and preserving the regenerative potential of HSCs. Effective MQC is essential for maintaining HSC function over time and preventing exhaustion, especially under stress conditions [124]. Following hematopoietic stem cell transplantation, mitochondrial transfer is crucial in supporting the recovery and engraftment of transplanted HSCs. Donor-derived stromal cells transfer functional mitochondria to HSCs, improving their survival and enhancing their capacity to repopulate the BM niche [124, 125]. This interaction accelerates hematopoietic recovery and immune reconstitution, particularly in the post-transplant setting.

The role of mitochondrial transfer in hematopoietic diseases

While mitochondrial transfer is essential for normal hematopoiesis, its dysregulation contributes to the pathogenesis of hematopoietic malignancies and complications in HSCT [126]. In AML, mitochondrial transfer from BMSCs supports the survival and metabolic flexibility of leukemic blasts. TNT-mediated transfer provides AML cells with functional mitochondria, enabling them to adapt to oxidative stress and chemotherapeutic agents. This transfer increases OXPHOS activity and ATP production in leukemic cells, promoting chemoresistance and disease progression. Therapeutic strategies targeting NOX2 or disrupting TNT formation have shown promise in reducing mitochondrial transfer and sensitizing AML cells to treatment [121, 122]. Like AML, mitochondrial transfer from BMSCs protects ALL cells from oxidative stress, contributing to chemoresistance. Inhibition of TNT formation with microtubule inhibitors, such as vincristine, has demonstrated the potential to overcome this resistance, offering new therapeutic avenues in ALL [127]. The senescence and metabolic state of BMSCs significantly impact mitochondrial transfer and transplantation outcomes. High mesenchymal stem cell (MSC) senescence is associated with impaired mitochondrial transfer, leading to increased graft-versus-host disease (GvHD) due to insufficient immune modulation. Conversely, low MSC senescence promotes mitochondrial transfer to immune cells, creating an immunosuppressive environment that increases relapse risk. Interventions like nicotinamide supplementation can restore mitochondrial function in senescent MSCs, balancing GvHD and graft-versus-leukemia responses [128]. Mitochondrial transfer is a critical mechanism in the BM microenvironment, shaping HSC metabolism, function, and stress response. While it supports normal hematopoiesis and regenerative processes, its dysregulation contributes to hematopoietic malignancies and transplant complications. Understanding the mechanisms and impacts of mitochondrial transfer provides a foundation for developing innovative therapeutic strategies to enhance HSC function and combat hematopoietic disorders.

Conclusion and prospects

MQC is a highly interconnected process that integrates mitophagy, biogenesis, fission, and fusion to maintain mitochondrial homeostasis in HSCs. Mitophagy selectively removes damaged mitochondria, preventing the accumulation of dysfunctional organelles, while mitochondrial biogenesis replenishes the mitochondrial network by generating new functional mitochondria. These processes must be tightly balanced, as excessive mitophagy without sufficient biogenesis leads to mitochondrial depletion, whereas excessive biogenesis without adequate mitophagy results in mitochondrial dysfunction and ROS accumulation. Additionally, mitochondrial fission facilitates mitophagy by segregating damaged portions of mitochondria for degradation, while mitochondrial fusion supports metabolic adaptation by enabling the exchange of mitochondrial contents. Disruptions in these pathways can lead to impaired HSC function, increased oxidative stress, and hematopoietic failure. Through mitophagy, mitochondrial biogenesis, and mitochondrial transfer mechanisms, HSCs dynamically regulate their metabolic states, effectively resist oxidative stress, repair damage, and sustain their self-renewal and differentiation potentials. Recent studies have identified critical regulatory molecules and signaling pathways in MQC processes. Additionally, bone marrow stromal cells support HSC survival and functional repair under stress conditions through mitochondrial transfer, further emphasizing the importance of the hematopoietic microenvironment in metabolic regulation.

Despite significant advancements in understanding the connection between MQC and HSCs, numerous questions remain unanswered. First, the coordinated interactions among different MQC mechanisms and their dynamic regulatory networks are not fully elucidated. For example, the synergistic roles of mitophagy and mitochondrial biogenesis in maintaining HSC homeostasis are still unclear. Second, the specific mechanisms by which MQC dysfunction contributes to hematopoietic diseases, including the maintenance of LSCs and chemotherapy resistance, require further exploration. Furthermore, developing innovative therapeutic strategies that target MQC pathways holds significant clinical promise. Approaches such as enhancing mitophagy or facilitating mitochondrial transfer could improve HSC function and lead to better treatment outcomes. Several clinical trials are currently exploring therapeutic strategies targeting mitochondrial quality control in hematopoietic and other diseases. For example, mitochondrial-targeted antioxidants such as MitoQ and SkQ1 are under investigation for their potential to mitigate oxidative stress-related damage in stem cells [129]. Additionally, trials investigating autophagy-enhancing compounds such as rapamycin analogs highlight the relevance of modulating mitophagy to improve HSC transplantation outcomes [56]. Despite these advances, there remains a significant gap in translating mitochondrial quality control findings into clinical practice, underscoring the need for further research in this area.

In the future, rapid advancements in single-cell technologies, metabolomics, and gene-editing tools will enable researchers to uncover the molecular mechanisms and dynamic regulatory patterns of MQC in HSCs with greater precision. Investigating how MQC influences HSC fate decisions under stress conditions or in disease contexts will provide novel insights into the diagnosis and treatment of hematopoietic disorders. Moreover, developing therapeutic drugs that target MQC, such as enhancing mitophagy or regulating redox balance, could provide breakthrough strategies for restoring stem cell function and advancing regenerative medicine.

In conclusion, MQC is a fundamental mechanism underlying HSC function and regulation. Ongoing research in this field not only enhances our understanding of stem cell biology but also identifies promising therapeutic targets for treating hematopoietic diseases. Advances in this area will bridge the gap between HSC biology and clinical applications, providing new hope for improving patient outcomes.