Mitochondria in the maintenance of hematopoietic stem cells: new perspectives and opportunities

Abstract

The hematopoietic system produces new blood cells throughout life. Mature blood cells all derived from a pool of rare long-lived hematopoietic stem cells (HSCs) that are mostly quiescent but occasionally divide and self-renew to maintain the stem cell pool and to insure the continuous replenishment of blood cells. Mitochondria have recently emerged as critical not only for HSC differentiation and commitment but also for HSC homeostasis. Mitochondria are dynamic organelles that orchestrate a number of fundamental metabolic and signaling processes, producing most of the cellular energy via oxidative phosphorylation. HSCs have a relatively high amount of mitochondria that are mostly inactive. Here, we review recent advances in our understanding of the role of mitochondria in HSC homeostasis and discuss, among other topics, how mitochondrial dynamism and quality control might be implicated in HSC fate, self-renewal, and regenerative potential.

Figure 1.

Transition from glycolysis to oxidative phosphorylation during HSC differentiation. Normal HSCs are known to be located in a low-oxygen niche environment and rely mostly on glycolysis. HSC differentiation is associated with elevation of ROS, mammalian target of rapamycin (mTOR) activation, enhanced mitochondrial biogenesis, and a switch to oxidative phosphorylation (OXPHOS) and increased oxygen consumption. ADP, adenosine 5′-diphosphate; ATP, adenosine triphosphate; Diff, differentiated cell; ETC, electron transport chain; TCA, tricarboxylic acid.

Figure 2.

Multiple mitochondrial processes regulate HSCs. Red arrows show the mitochondrial-related processes. Blue arrows show the secondary effects. DRP1, dynamin-related protein 1; MFN2, mitofusin 2; NAD, nicotinamide adenine dinucleotide (oxidized).

Figure 3.

Mitochondrial metabolism regulates the epigenome. Some of the metabolites produced by OXPHOS and TCA cycle (including NAD and acetylCoA) serve as cofactors for, or used by, epigenetic factors like sirtuins (SIRTs) and histone acetyl-transferases. Δψ, mitochondrial membrane potential; CoA, coenzyme A; GSH, glutathione; GSSH, oxidized glutathione; LDH, lactate dehydrogenase; NADP, NAD phosphate; NADPH, reduced NADP; PEP, phosphoenolpyruvate; PFK, phosphofructokinase; PK, pyruvate kinase.