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.

Keywords: Hematopoietic stem cell; Mitochondrial biogenesis; Mitochondrial dynamics; Mitochondrial metabolism; Mitochondrial quality control; Mitochondrial transfer; Mitophagy.

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

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

Fig. 3

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

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

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