Autophagy and Metabolism in Normal and Malignant Hematopoiesis

Abstract

The hematopoietic system relies on regulation of both metabolism and autophagy to maintain its homeostasis, ensuring the self-renewal and multipotent differentiation potential of hematopoietic stem cells (HSCs). HSCs display a distinct metabolic profile from that of their differentiated progeny, while metabolic rewiring from glycolysis to oxidative phosphorylation (OXPHOS) has been shown to be crucial for effective hematopoietic differentiation. Autophagy-mediated regulation of metabolism modulates the distinct characteristics of quiescent and differentiating hematopoietic cells. In particular, mitophagy determines the cellular mitochondrial content, thus modifying the level of OXPHOS at the different differentiation stages of hematopoietic cells, while, at the same time, it ensures the building blocks and energy for differentiation. Aberrations in both the metabolic status and regulation of the autophagic machinery are implicated in the development of hematologic malignancies, especially in leukemogenesis. In this review, we aim to investigate the role of metabolism and autophagy, as well as their interconnections, in normal and malignant hematopoiesis.

Mitochondria and Their Relationship with Common Genetic Abnormalities in Hematologic Malignancies

“…Mitophagy is important both in normal hematopoietic cell development and in various hematologic malignancies, discussed in detail in a recent review by Stergiou and Kapsogeorgou [88]. In AML, decreased mitophagy was shown to reduce cell proliferation.…”

“…In addition, mitophagy was found to be prominent in the myeloid lineage in MDS. Interestingly, mitophagy receptor, BNIP3 and NIX, expressions were decreased in MDS, latter in the high-risk group [88][89][90][91][92][93]. Mitophagy inhibitors and inducers are listed in Section 4, Table 3.…”

High Metabolic Dependence on Oxidative Phosphorylation Drives Sensitivity to Metformin Treatment in MLL/AF9 Acute Myeloid Leukemia

“…Meanwhile, metabolites generated from metabolic pathways also contribute to signaling functions, remodeling the epigenome, and altering the expression of specific sets of genes that can initiate and support cancer development [7]. Accumulating data have demonstrated a role of metabolic reprogramming, including glycolysis, oxidative phosphorylation (OXPHOS), and fatty acid metabolism in AML [8][9][10]. However, substantial studies have shown that the metabolic heterogeneity among AML patients results from multiple factors, including gene mutations and BM microenvironment [11,12].…”

Novel Oleanane-Type Triterpene Glycosides from the Saponaria officinalis L. Seeds and Apoptosis-Inducing Activity via Mitochondria

“…Mitophagy is defined as mitochondria-selective autophagy and plays a role in the elimination of defective mitochondria [31]. Several reports have suggested that depolarization of the mitochondrial membrane potential and ROS production are involved in mitophagy [32][33][34].…”