Mitochondrial Contributions to Hematopoietic Stem Cell Aging

Abstract

Mitochondrial dysfunction and stem cell exhaustion are two hallmarks of aging. In the hematopoietic system, aging is linked to imbalanced immune response and reduced regenerative capacity in hematopoietic stem cells (HSCs), as well as an increased predisposition to a spectrum of diseases, including myelodysplastic syndrome and acute myeloid leukemia. Myeloid-biased differentiation and loss of polarity are distinct features of aged HSCs, which generally exhibit enhanced mitochondrial oxidative phosphorylation and increased production of reactive oxygen species (ROS), suggesting a direct role for mitochondria in the degenerative process. Here, we provide an overview of current knowledge of the mitochondrial mechanisms that contribute to age-related phenotypes in HSCs. These include mitochondrial ROS production, alteration/activation of mitochondrial metabolism, the quality control pathway of mitochondria, and inflammation. Greater understanding of the key machineries of HSC aging will allow us to identify new therapeutic targets for preventing, delaying, or even reversing aspects of this process.

Keywords: ROS; aging; hematopoiesis; hematopoietic stem cell; inflammation; mitochondrial metabolism; stem cell exhaustion.

Figure 1

Features of aged HSCs. Upon aging, hematopoietic stem cells (HSCs) acquire phenotypical and functional peculiar properties. Flow cytometry analysis of the murine bone marrow shows an increase in the phenotypic HSCs (defined as c-Kit⁺Sca-1⁺Lin⁻CD135⁻CD48⁻CD150⁺) in old (18 months old, bottom panel) mice (far left). The HSC pool includes balanced HSC, which in equal proportion differentiate in myeloid and lymphoid lineage (yellow, left); with age, the myeloid-biased differentiation prevails at the expense of lymphoid cells (left). The self-renewal capacity typical of HSCs is reduced upon aging (middle). Cytoskeletal polarity detected by CDC42 localization is lost in old HSCs where CDC42 expression is homogeneously distributed (right). Aged HSCs display the mitochondrial damage with the altered metabolism (far right).

Figure 2

Mitochondrial contribution to aging. Aging process shows dysregulation of several pathway involving the direct contribution of mitochondria. Mitochondrial reactive oxygen species (mtROS) accumulate after the impairment of the major antioxidant defense systems, consist of Superoxide dismutase 2 (SOD2) and Catalase, caused by the aged-related loss of FOXO3 and SIRT3 (grey). AKT/mTOR signaling is a key regulator of mitochondrial metabolism and, upon aging, its imbalance causes mtROS accumulation, mitochondrial biogenesis, and an altered metabolism. Inhibition of complex II of the electron transport chain (ETC) leads to oxygen hypersensitivity and premature aging of HSCs (pink). The mitochondrial unfolded protein response system (mtUPR) is affected by the aged-related loss of SIRT7, leading to accumulation of unfolded protein and mitochondrial stress (green). Accumulation of mtROS activates the NOD-, LRR-, and pyrin domain-containing 3 (NLRP3) inflammasome, which triggers the release of inflammatory cytokines, such as IL-1β and IL-18 (orange). Mitochondrial dysfunctions include accumulation of mtDNA mutations in aged HSCs (blue).