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.
Highlights
Luo et al recently demonstrated that mitochondrial stress activates the NLRP3 inflammasome in hematopoietic stem cells (HSCs) as part of the key role played by mitochondria in the inflammation process during aging [130]
We summarize accumulating evidence that support the concept that mitochondrial stress is one of the main drivers of stem cell deterioration with age
Since the studies of HSC aging have been performed, for the most part, in mouse models, it is crucial to determine whether these findings can be translated to humans
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. It has been shown that phenotypic HSCs in the bone marrow increase in frequency with age, while losing their functionality. The self-renewal capacity typical of HSCs is reduced the myeloid-biased differentiation prevails at the expense of lymphoid cells (left). Aged HSCs display the mitochondrial damage with the altered metabolism (far right). Mitochondrial reactive oxygen 2species accumulate theaged-related impairment majorcontribution antioxidant defense systems, consist of Superoxide dismutase (SOD2)(mtROS). Accumulation of activates the NOD-, LRR-, and pyrin domainThe mitochondrial unfolded protein response system (mtUPR) is affected by the aged-related loss of SIRT7, leading to containing 3 (NLRP3) inflammasome, which triggers the release of inflammatory cytokines, such as IL-1β and IL-18 (oraccumulation of unfolded protein and mitochondrial stress (green). Mitochondrial dysfunctions include accumulation of mtDNA mutations in aged HSCs (blue)
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