Mitochondria Turnover and Lysosomal Function in Hematopoietic Stem Cell Metabolism

Abstract

Hematopoietic stem cells (HSCs) reside in a hypoxic microenvironment that enables glycolysis-fueled metabolism and reduces oxidative stress. Nonetheless, metabolic regulation in organelles such as the mitochondria and lysosomes as well as autophagic processes have been implicated as essential for the determination of HSC cell fate. This review encompasses the current understanding of anaerobic metabolism in HSCs as well as the emerging roles of mitochondrial metabolism and lysosomal regulation for hematopoietic homeostasis.

Increasing Complexity of Molecular Landscapes in Human Hematopoietic Stem and Progenitor Cells during Development and Aging

“…A cell autonomous increase in human adult bone marrow HSC self-renewal has been considered as the main driving force for clonal hematopoiesis, rather than neutral genetic drift [ 252 ]. Although clonal hematopoiesis is often mediated by dysregulated epigenetic control mechanisms, other stressors, such as chronic low-grade inflammation (inflamm-aging) and alterations in cellular metabolism during aging, are thought to confer a competitive advantage to the expansion of the affected hematological clones [ 4 , 10 , 291 , 292 , 293 , 294 , 295 , 296 , 297 , 298 , 299 , 300 , 301 ]. Given the excellent comprehensive reviews on developmental- and age-related changes in HSC metabolism and/or inflamm-aging [ 10 , 292 , 293 , 294 , 295 , 296 , 297 , 298 , 299 ], we restrict this section to a brief overview of more recent studies on the role of mitochondria and lysosomes in regulating HSC fate before focusing on the contribution of inflamm-aging and altered metabolism to clonal hematopoiesis driven by mutations in the epigenetic modifier genes, DNMT3A , an epigenetic writer, and TET2 , an epigenetic eraser, both of which, as indicated above, play significant roles in CHIP development.…”

“…Metabolism controls HSPC function, in part by providing energy (ATP) and tricarboxylic acid (TCA) cycle metabolites [ 293 , 294 ]. ATP is produced by glycolysis, the conversion of glucose to pyruvate in the cell cytoplasm, and by oxidative phosphorylation, which involves the oxidation of pyruvate to acetyl-CoA via the mitochondrial TCA cycle [ 293 , 294 , 302 ].…”

“…Metabolism controls HSPC function, in part by providing energy (ATP) and tricarboxylic acid (TCA) cycle metabolites [ 293 , 294 ]. ATP is produced by glycolysis, the conversion of glucose to pyruvate in the cell cytoplasm, and by oxidative phosphorylation, which involves the oxidation of pyruvate to acetyl-CoA via the mitochondrial TCA cycle [ 293 , 294 , 302 ]. Under homeostatic conditions, adult bone marrow HSCs, which exist in a quiescent state in order to maintain their potency and as a protection from replicative and oxidative stress, principally rely on anaerobic glycolysis for their energy rather than mitochondrial oxidative phosphorylation, consequently limiting their levels of reactive oxygen species (ROS) [ 293 , 294 , 302 , 303 ].…”

“…ATP is produced by glycolysis, the conversion of glucose to pyruvate in the cell cytoplasm, and by oxidative phosphorylation, which involves the oxidation of pyruvate to acetyl-CoA via the mitochondrial TCA cycle [ 293 , 294 , 302 ]. Under homeostatic conditions, adult bone marrow HSCs, which exist in a quiescent state in order to maintain their potency and as a protection from replicative and oxidative stress, principally rely on anaerobic glycolysis for their energy rather than mitochondrial oxidative phosphorylation, consequently limiting their levels of reactive oxygen species (ROS) [ 293 , 294 , 302 , 303 ]. In contrast, fatty acid oxidation promotes HSC self-renewal and asymmetrical division [ 294 , 304 ], while HSC differentiation is associated with a switch from glycolysis to mitochondrial oxidative phosphorylation, which moderately increases ROS levels [ 293 , 302 , 305 ].…”

“…Under homeostatic conditions, adult bone marrow HSCs, which exist in a quiescent state in order to maintain their potency and as a protection from replicative and oxidative stress, principally rely on anaerobic glycolysis for their energy rather than mitochondrial oxidative phosphorylation, consequently limiting their levels of reactive oxygen species (ROS) [ 293 , 294 , 302 , 303 ]. In contrast, fatty acid oxidation promotes HSC self-renewal and asymmetrical division [ 294 , 304 ], while HSC differentiation is associated with a switch from glycolysis to mitochondrial oxidative phosphorylation, which moderately increases ROS levels [ 293 , 302 , 305 ]. Mitochondria and lysosomes, as nutrient signaling and sensing hubs, and crosstalk between these organelles, are now considered important elements for regulating HSC fate and function [ 10 , 293 , 294 , 302 , 306 , 307 ].…”