Genetic models of mitochondrial impact on HSCs
| Gene . | HSC profile . | Mitochondrial profile . | Implicated mechanism . | References . |
|---|---|---|---|---|
| Stk1 (LKB1) | Loss of LKB1 leads to severe pancytopenia, lethality; loss of HSC quiescence, exhaustion of the HSC pool, reduced HSC repopulating potential in vivo | Defects in mitochondrial biogenesis, reduced MMP and ATP in HSCs, defects in centrosomes and mitotic spindles, aneuploidy | AMPK/mTOR- FOXO-independent | 20,70,71 |
| Bid | Loss of BID phosphorylation results in loss of HSC quiescence, exhaustion of the HSC pool, reduction of HSC-repopulating potential in vivo | Increase in mitochondrial BID and mitochondrial oxidative stress | ATM-mediated BID phosphorylation maintains HSC quiescence | 21 |
| Mtch2 | Loss of MTCH2 increases mitochondrial OXPHOS, enhances HSC and progenitor cell entry into cycle | Elevated OXPHOS, increase in mitochondrial size, increase in ATP and ROS levels, protection from irradiation-induced apoptosis | MTCH2 is a negative regulator of mitochondrial OXPHOS downstream of BID | 72 |
| Hspa9 (Mortalin) | Mortalin KD led to loss of HSC quiescence and impaired ability to repopulate in vivo | Downregulation of cyclin-dependent kinase inhibitor- and antioxidant-related genes DJ-1 bound to Mortalin, acts as a negative regulator of ROS | Mortalin/DJ-1 complex guards against mitochondrial oxidative stress and is indispensable for the maintenance of HSCs | 22 |
| Tsc1 | TSC1−/− leads to loss of HSC quiescence and self-renewal, mTOR activation treated by an anti-ROS approach | Increased ROS and mitochondrial biogenesis | TSC-mTOR pathway maintains the quiescence and function of HSCs by repressing ROS production | 7 |
| polg | POLG mutator mice (proofreading-defective mitochondrial DNA polymerase) exhibit some similarity to HSC aging including anemia, lymphopenia, and myeloid lineage skewing; however, the HSC pool is maintained while HSC differentiation is blocked | mtDNA mutations | Intact mitochondrial function is required for multilineage stem cell differentiation, but mitochondrial DNA mutations are not a primary driver of somatic stem cell aging. | 14 |
| Uqcrfs1 (Rieske Iron-Sulfur Protein [RISP]) | RISP−/− results in loss of fetal HSC quiescence and defective repopulation ability, impaired fetal liver HSC differentiation, depletion of myeloid progenitors and erythroid precursors, severe pancytopenia | Accumulation of 2HG, fumarate and succinate leading to histone and DNA hypermethylation, histone hypoacetylation | Mitochondrial involvement in HSC maintenance and differentiation | 41 |
| Foxo3 | FOXO3−/− loss of HSC quiescence decreased HSC pool and in vivo competitive repopulation ability, myeloproliferation lack of rescue of in vivo repopulation ability by antioxidant therapy | Increased ROS, increased mitochondrial content and membrane potential, reduced ATP, increased glycolysis, reduced OXPHOS, fragmented mitochondria | Defective mitochondria might mediate HSC defects | 8,16 |
| Ptpmt1 | PTPMT1−/− led to cell cycle modulations, block in differentiation; HSC pool increased by 40-fold and a block in in vivo repopulation ability | Reduced oxygen consumption, enhanced glycolysis, enhanced fatty acid metabolism, activated AMPK, accumulation of PIP substrates, enhanced UCP2 activity | PTPMT1 is implicated in the metabolic regulation of HSC function | 23 |
| Mfn2 | MFN2−/− leads to myeloid-biased lineage commitment | Mfn2 increases buffering of intracellular Ca++ through its endoplasmic reticulum–mitochondria tethering, negatively impacting NFAT | 47 | |
| Pparg | Loss of PPAR-δ leads to loss of HSC maintenance | PML–PPAR-δ controls the asymmetric division of HSCs | 40 |
| Gene . | HSC profile . | Mitochondrial profile . | Implicated mechanism . | References . |
|---|---|---|---|---|
| Stk1 (LKB1) | Loss of LKB1 leads to severe pancytopenia, lethality; loss of HSC quiescence, exhaustion of the HSC pool, reduced HSC repopulating potential in vivo | Defects in mitochondrial biogenesis, reduced MMP and ATP in HSCs, defects in centrosomes and mitotic spindles, aneuploidy | AMPK/mTOR- FOXO-independent | 20,70,71 |
| Bid | Loss of BID phosphorylation results in loss of HSC quiescence, exhaustion of the HSC pool, reduction of HSC-repopulating potential in vivo | Increase in mitochondrial BID and mitochondrial oxidative stress | ATM-mediated BID phosphorylation maintains HSC quiescence | 21 |
| Mtch2 | Loss of MTCH2 increases mitochondrial OXPHOS, enhances HSC and progenitor cell entry into cycle | Elevated OXPHOS, increase in mitochondrial size, increase in ATP and ROS levels, protection from irradiation-induced apoptosis | MTCH2 is a negative regulator of mitochondrial OXPHOS downstream of BID | 72 |
| Hspa9 (Mortalin) | Mortalin KD led to loss of HSC quiescence and impaired ability to repopulate in vivo | Downregulation of cyclin-dependent kinase inhibitor- and antioxidant-related genes DJ-1 bound to Mortalin, acts as a negative regulator of ROS | Mortalin/DJ-1 complex guards against mitochondrial oxidative stress and is indispensable for the maintenance of HSCs | 22 |
| Tsc1 | TSC1−/− leads to loss of HSC quiescence and self-renewal, mTOR activation treated by an anti-ROS approach | Increased ROS and mitochondrial biogenesis | TSC-mTOR pathway maintains the quiescence and function of HSCs by repressing ROS production | 7 |
| polg | POLG mutator mice (proofreading-defective mitochondrial DNA polymerase) exhibit some similarity to HSC aging including anemia, lymphopenia, and myeloid lineage skewing; however, the HSC pool is maintained while HSC differentiation is blocked | mtDNA mutations | Intact mitochondrial function is required for multilineage stem cell differentiation, but mitochondrial DNA mutations are not a primary driver of somatic stem cell aging. | 14 |
| Uqcrfs1 (Rieske Iron-Sulfur Protein [RISP]) | RISP−/− results in loss of fetal HSC quiescence and defective repopulation ability, impaired fetal liver HSC differentiation, depletion of myeloid progenitors and erythroid precursors, severe pancytopenia | Accumulation of 2HG, fumarate and succinate leading to histone and DNA hypermethylation, histone hypoacetylation | Mitochondrial involvement in HSC maintenance and differentiation | 41 |
| Foxo3 | FOXO3−/− loss of HSC quiescence decreased HSC pool and in vivo competitive repopulation ability, myeloproliferation lack of rescue of in vivo repopulation ability by antioxidant therapy | Increased ROS, increased mitochondrial content and membrane potential, reduced ATP, increased glycolysis, reduced OXPHOS, fragmented mitochondria | Defective mitochondria might mediate HSC defects | 8,16 |
| Ptpmt1 | PTPMT1−/− led to cell cycle modulations, block in differentiation; HSC pool increased by 40-fold and a block in in vivo repopulation ability | Reduced oxygen consumption, enhanced glycolysis, enhanced fatty acid metabolism, activated AMPK, accumulation of PIP substrates, enhanced UCP2 activity | PTPMT1 is implicated in the metabolic regulation of HSC function | 23 |
| Mfn2 | MFN2−/− leads to myeloid-biased lineage commitment | Mfn2 increases buffering of intracellular Ca++ through its endoplasmic reticulum–mitochondria tethering, negatively impacting NFAT | 47 | |
| Pparg | Loss of PPAR-δ leads to loss of HSC maintenance | PML–PPAR-δ controls the asymmetric division of HSCs | 40 |
2HG, 2-hydroxyglutarate; AMPK, 5′ AMP-activated protein kinase; ATM, ataxia–telangiectasia; BID, BH3 interacting-domain death agonist; KD, knockdown; MTCH2, mitochondrial carrier homolog 2; PIP, phosphatidylinositol phosphate; PML, promyelocytic leukemia; UCP, uncoupling protein; TSC, tuberous sclerosis protein.