Fig. 3
From: Role of reactive oxygen species in myelodysplastic syndromes
a Multiple mitochondrial processes regulate HSCs. HSCs are exceedingly sensitive to ROS (mainly generated by mitochondrial metabolism) levels, which can directly influence their differentiation and commitment. Excessive ROS levels invariably cause HSC pool exhaustion. Metabolites (e.g., fumarate, succinate, NAD, and acetyl-CoA), produced by mitochondria through OXPHOS and the TCA cycle, could impact the epigenetic landscape. For example, fatty acid oxidation in HSCs is required to support acetyl-CoA production. Meanwhile, the mitochondrial dynamic regulatory protein Mfn2 inhibits NFAT activity by a negative effect on intracellular calcium ions, thereby maintaining HSCs. Heightened calcium signaling prompts mitochondrial activity and participates in HSC division. In addition, mitochondrial dynamics and mitophagy are an integral part of HSC maintenance. Specifically, mitochondrial dynamics (e.g., fusion, fission, and motility) together determine mitochondrial morphology and are conducive to mitochondrial quality control and cellular stress response, while mitophagy can sweep away impaired mitochondria and contribute to the normal function of HSCs. Red arrows represent mitochondrial-related processes, while blue arrows stand for secondary effects. b Assembly of NOX isoforms. The NOX2 complex is composed of cytosolic subunits (p47phox, p40phox, and p67phox), a small GTPase Rac1/2, and membrane subunits (gp91phox, and p22phox). NOX1 is constituted of the NOX1 catalytic subunit (a homolog of gp91phox), NOXO1 (a homolog of p47phox), NOXA1 (a homolog of p67phox), and Rac1 subunit. The structure of NOX3 is similar to NOX1/2. However, NOX4 constitutes membrane subunits p22phox, and poldip2 is significantly different from other NOXs. NOX5 boasts a special N-terminal domain that harbors four Ca2+ binding sites and an EF-hand domain. The DUOX1/2 has a unique N-terminal domain and EF hand-type Ca2+-binding pockets. The activation of NOX1-3 needs cytosolic subunits, while NOX4 requires p22phox and poldip2. Ca2+ that binds to the EF-hand domains is demanded in the activation of NOX5 and DUOX1/2