Imaging Cellular Metabolism

The genomic characterization of acute myeloid leukemia (AML) by DNA sequencing has illuminated subclasses of the disease, with distinct driver mutations, that might be responsive to targeted therapies. Approximately 15-23% of AML genomes harbor mutations in one of two isoforms of isocitrate dehydrogenase (IDH1 or IDH2). These enzymes are constitutive mediators of basic cellular metabolism, but their mutated forms in cancer synthesize an abnormal metabolite, 2- hydroxyglutarate, that in turn acts as a competitive inhibitor of multiple gene regulatory enzymes. As a result, leukemic IDH mutations cause changes in genome structure and gene activity, culminating in an arrest of normal myeloid differentiation. These discoveries have motivated the development of a new class of selective small molecules with the ability to inhibit the mutant IDH enzymes while sparing normal cellular metabolism. These agents have shown promising anti-leukemic activity in animal models and early clinical trials, and are now entering Phase 3 study. This review will focus on the growing preclinical and clinical data evaluating IDH inhibitors for the treatment of IDH-mutated AML. These data suggest that inducing cellular differentiation is central to the mechanism of clinical efficacy for IDH inhibitors, while also mediating toxicity for patients who experience IDH Differentiation Syndrome. Ongoing trials are studying the efficacy of IDH inhibitors in combination with other AML therapies, both to evaluate potential synergistic combinations as well as to identify the appropriate place for IDH inhibitors within existing standard-of-care regimens.

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Peptide intermediates in the cellular metabolism of insulin.

Journal of Biological Chemistry ◽

10.1016/s0021-9258(18)34245-5 ◽

1982 ◽

Vol 257 (15) ◽

pp. 9078-9085 ◽

Cited By ~ 7

Author(s):

R K Assoian ◽

H S Tager

Keyword(s):

Cellular Metabolism

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Redox Regulation of Lipid Mobilization in Adipose Tissues

Antioxidants ◽

10.3390/antiox10071090 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1090

Author(s):

Ursula Abou-Rjeileh ◽

G. Andres Contreras

Keyword(s):

Adipose Tissue ◽

Energy Metabolism ◽

Redox Regulation ◽

Cellular Metabolism ◽

Antioxidant Response ◽

Redox Signaling ◽

Nitrogen Species ◽

Adipose Tissues ◽

Lipid Mobilization ◽

Cellular Processes

Lipid mobilization in adipose tissues, which includes lipogenesis and lipolysis, is a paramount process in regulating systemic energy metabolism. Reactive oxygen and nitrogen species (ROS and RNS) are byproducts of cellular metabolism that exert signaling functions in several cellular processes, including lipolysis and lipogenesis. During lipolysis, the adipose tissue generates ROS and RNS and thus requires a robust antioxidant response to maintain tight regulation of redox signaling. This review will discuss the production of ROS and RNS within the adipose tissue, their role in regulating lipolysis and lipogenesis, and the implications of antioxidants on lipid mobilization.

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Hepatic Manifestations of Mendelian Disorders of Cholesterol Biosynthesis and Cellular Metabolism

Clinical Liver Disease ◽

10.1002/cld.1154 ◽

2021 ◽

Author(s):

Alanna Strong ◽

Rebecca Ganetzky ◽

Daniel J. Rader

Keyword(s):

Cholesterol Biosynthesis ◽

Cellular Metabolism ◽

Mendelian Disorders

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LOSS OF GLUTATHIONE PEROXIDASE 1 ATTENUATES COLITIS AND IS CRITICAL IN ACTIVATING EPITHELIAL REGENERATIVE RESPONSES

Inflammatory Bowel Diseases ◽

10.1093/ibd/izaa347.060 ◽

2021 ◽

Vol 27 (Supplement_1) ◽

pp. S27-S27

Author(s):

Jared Hendren ◽

Koral Kasnyik ◽

Christopher Williams ◽

Sarah Short

Keyword(s):

Stem Cell ◽

Glutathione Peroxidase ◽

Target Genes ◽

Cell Function ◽

Intestinal Inflammation ◽

Cellular Metabolism ◽

Intestinal Injury ◽

Gene Set Enrichment Analysis ◽

Intestinal Cell ◽

Glutathione Peroxidase 1

Abstract Many selenium-containing “selenoproteins” function as antioxidants, and work by our lab and others has demonstrated that selenoproteins often protect against intestinal inflammatory diseases, including colitis. Glutathione peroxidase 1 (GPx1) is a ubiquitous, mitochondrial and cytosolic selenoprotein which catalyzes the reduction of hydrogen peroxide by glutathione. Previously, we determined that despite its antioxidant role, loss of GPx1 greatly reduced disease severity in the dextran sodium sulfate (DSS) colitis model. Furthermore, GPx1 loss increased baseline intestinal cell proliferation, enhanced enteroid plating efficiency, and induced expression of stem cell-associated genes, such as Lgr5. Next, we aimed to determine the mechanism by which GPx1 modifies response to DSS. We observed that GPx1 is increased in colonic tissues from DSS-treated mice as compared to nontreated controls, suggesting that GPx1 may functionally contribute to intestinal injury responses. While GPx1 is expressed in both intestinal epithelial and immune cells, in situ hybridization to visualize Gpx1 identified epithelial cells as the most highly expressing cell type, with the greatest Gpx1 upregulation observed in wound-adjacent and regenerative crypts. Next, we investigated whether GPx1 loss affects stem cell function after injury. Here, we determined that both proliferation (p<0.01) and Lgr5 expression (p<0.05) were increased in the crypts of Gpx1-/- DSS-treated mice in comparison to WT controls. Similarly, organoids established from ulcerative colitis tissue displayed increased growth rates (p<0.01), expression of stem cell and Wnt target genes such as AXIN2 (p<0.0001) and LGR5 (p<0.01), and proliferation (p<0.05) following GPX1 knockdown. Together, these results indicate that GPx1 has an epithelial-cell autonomous role, and that its loss activates stem cell and proliferative responses which may both protect from intestinal injury and promote healing. Interestingly, recent research has highlighted the role of cellular metabolism in maintaining intestinal stem cell function, and GPx1 has previously been implicated in these processes. RNA-sequencing from DSS-treated mice and gene set enrichment analysis identified a positive association with oxidative phosphorylation-associated genes in Gpx1-/- mice (NES: 1.78; FDR q-val: 0.01), suggesting altered metabolism which may favor stem cell function. Further analysis of cellular metabolism using GPX1 knockdown colorectal cancer cells observed higher basal respiration (p<0.0001) and ATP generation (p<0.0001). Together, these results suggest that unlike other intestinal selenoproteins studied to date, loss of GPx1 augments stem cell injury responses to protect against intestinal inflammation, likely via augmenting epithelial regenerative responses.

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