Table 1 Genes targeting mitochondrial quality control to regulate HSC function

Mitophagy

PINK1(PTEN-Induced Putative Kinase 1)

Accumulates on damaged mitochondria, recruits Parkin to initiate mitophagy

Maintains mitochondrial quality and reduces ROS in HSCs

Enhances HSC functionality in aging or stress

[9]

Parkin (Parkinson Protein 2, E3 Ubiquitin Ligase)

Ubiquitinates mitochondrial proteins, marking them for degradation

Maintains HSC quiescence and prevents oxidative stress

Improves HSC transplantation outcomes

[9]

BNIP3(BCL2/adenovirus E1B 19 kDa protein-interacting protein 3)

Interacts with LC3 to mediate mitochondrial clearance under hypoxic conditions

Protects HSCs from oxidative stress and ensures long-term hematopoiesis

Protects HSCs during aging

[31]

FUNDC1(FUN14 Domain Containing 1)

Hypoxia-inducible receptor for mitophagy

Maintains HSC function in low-oxygen bone marrow environments

Enhances HSC function under hypoxic stress

[35]

ATAD3A (ATPase Family AAA Domain Containing 3 A)

Interacts with mitochondrial channels Tom40 and Tim23 to promote mitophagy

Maintains mitochondrial integrity and prevents HSC dysfunction

Improves mitochondrial function in stressed HSCs

[36, 37]

NIX1 (Nip3-like protein X)

Regulates mitophagy during erythrocyte maturation

Facilitates mitochondrial clearance in red cell development

Potential target for anemia treatment

[38]

OGT (O-Linked N-Acetylglucosamine Transferase)

Regulates mitophagy via PINK1-dependent pathways

Controls HSC stress response and self-renewal by maintaining mitochondrial health

Enhances HSC performance under stress

[8]

AMPK (AMP-Activated Protein Kinase)

Activates mitophagy via ULK1 and suppresses mTOR signaling

Promotes HSC metabolic adaptation and stress resilience

Enhances HSC resilience to metabolic stress

[39]

SIRT3 (Sirtuin 3)

Mitochondrial deacetylase that regulates oxidative phosphorylation and mitophagy

Reduces ROS levels and preserves HSC functionality

Delays HSC aging and enhances regeneration

[40]

ULK1(Unc-51 Like Autophagy Activating Kinase 1)

Key autophagy initiator regulating mitochondrial clearance

Activates mitophagy during metabolic stress, preserving HSC function

Enhances HSC maintenance under stress

[41]

ATG5 (Autophagy Related 5)

Essential for autophagosome formation and mitochondrial clearance

Maintains mitochondrial quality and HSC self-renewal

Target for mitigating HSC exhaustion

[42]

ATG7(Autophagy Related 7)

Central autophagy regulator critical for autophagosome formation

Maintains metabolic balance in HSCs

Enhances HSC regenerative capacity

[27, 42, 43]

LC3 (Microtubule-Associated Protein 1 A/1B-Light Chain 3)

Core marker and participant in autophagosome formation

Essential for mitophagy and mitochondrial clearance in HSCs

Critical target in autophagy-based therapies

[25]

P62 (Sequestosome 1)

Adaptor protein facilitating mitophagy via LC3 interaction

Supports mitochondrial turnover and oxidative stress resilience

Key regulator in autophagy-related therapeutic strategies

[44]

NKX2-3 (NK2 Homeobox 3)

Regulates mitochondrial autophagy and oxidative metabolism

Promotes HSC metabolic stability

Novel potential target in HSC research

[7]

Mitochondrial Fission

FIS1 (Mitochondrial Fission 1 Protein)

Regulates mitochondrial fission and mitophagy

Maintains mitochondrial dynamics and HSC stemness

Disrupting FIS1 can impair leukemic stem cells

[45]

DRP1 (Dynamin-related protein 1)

Mediates mitochondrial fission and contributes to mitochondrial quality control

Supports mitochondrial remodeling and metabolic adaptation

Potential therapeutic target in leukemic stem cells

[46]

Mitochondrial Fusion

MFN1 (Mitofusin 1)

Promotes mitochondrial fusion to maintain mitochondrial function

Ensures HSC mitochondrial network stability

Enhances stem cell regenerative potential

[47]

MFN2 (Mitofusin 2)

Regulates mitochondrial fusion and prevents excessive fission

Prevents mitochondrial fragmentation in HSCs

Therapeutic target for metabolic disorders

[47]

OPA1 (Optic Atrophy 1)

Maintains mitochondrial cristae integrity and fusion capacity

Supports HSC energy homeostasis

Enhances hematopoietic cell function

[48]

Mitochondrial Biogenesis

PPAR (Peroxisome Proliferator-Activated Receptor)

Regulates mitochondrial metabolism and oxidative phosphorylation

Enhances HSC energy efficiency and stress adaptation

Target for metabolic reprogramming in HSCs

[49]

TFAM (Transcription factor A)

Controls mitochondrial DNA transcription and replication

Essential for mitochondrial genome stability in HSCs

Enhances HSC proliferation and function

[50]

NRF1 (Nuclear respiratory factor 1)

Transcription factor regulating mitochondrial biogenesis

Supports mitochondrial network expansion

Target for enhancing metabolic resilience

[51]

PGC-1α (Peroxisome proliferator-activated receptor-γ coactivator 1α)

Master regulator of mitochondrial biogenesis and oxidative metabolism

Promotes mitochondrial expansion during HSC differentiation

Target for metabolic-based stem cell therapy

[52]

Other Mitochondrial Quality Control Regulators

FOXO3 (Forkhead Box O3)

Regulates antioxidant pathways and metabolic adaptation, indirectly modulating mitophagy

Promotes HSC quiescence and longevity

Delays HSC aging and enhances hematopoietic regeneration

[53, 54]

FANCD2 (Fanconi Anemia Complementation Group D2)

Protects HSCs from DNA damage and oxidative stress

Ensures genomic stability and HSC longevity

Therapeutic target for preventing HSC exhaustion

[29]

TGFβ1 (Transforming Growth Factor Beta 1)

Modulates HSC quiescence and proliferation

Controls mitophagy indirectly through cellular stress pathways

Target to modulate HSC quiescence and expansion

[55]

MTORC1 (Mechanistic Target of Rapamycin Complex 1)

Negative regulator of autophagy

Regulates autophagy through nutrient-sensing pathways

MTORC1 inhibition enhances mitophagy in stressed HSCs

[56]

SRSF2 (Serine and arginine-rich splicing Factor 2)

Regulates RNA splicing affecting mitophagy-related pathways

Impacts HSC functionality and stemness

Potential target for improving HSC regenerative capacity

[57]

Connexin-43(Gap Junction Alpha-1 Protein)

Regulates mitochondrial fission and mitophagy via Drp1-PINK1 axis

Balances mitochondrial dynamics during HSC division, supporting quiescence

Improves HSC regeneration post-transplantation

[58]