scholarly journals HIF-1α Is a Metabolic Switch between Glycolytic-Driven Migration and Oxidative Phosphorylation-Driven Immunosuppression of Tregs in Glioblastoma

Cell Reports ◽  
2019 ◽  
Vol 27 (1) ◽  
pp. 226-237.e4 ◽  
Author(s):  
Jason Miska ◽  
Catalina Lee-Chang ◽  
Aida Rashidi ◽  
Megan E. Muroski ◽  
Alan L. Chang ◽  
...  
Keyword(s):  
Oxidative Phosphorylation ◽  
Metabolic Switch

scholarly journals Wild-Type p53 Promotes Cancer Metabolic Switch by Inducing PUMA-Dependent Suppression of Oxidative Phosphorylation

Cancer Cell ◽  
2019 ◽  
Vol 35 (2) ◽  
pp. 191-203.e8 ◽  
Author(s):  
Jinchul Kim ◽  
Lili Yu ◽  
Wancheng Chen ◽  
Yanxia Xu ◽  
Meng Wu ◽  
...  
Keyword(s):  
Oxidative Phosphorylation ◽  
Wild Type ◽  
Metabolic Switch ◽  
Wild Type P53

scholarly journals ITGB2-mediated metabolic switch in CAFs promotes OSCC proliferation by oxidation of NADH in mitochondrial oxidative phosphorylation system

Theranostics ◽  
2020 ◽  
Vol 10 (26) ◽  
pp. 12044-12059
Author(s):  
Xiaoxin Zhang ◽  
Yingchun Dong ◽  
Mengxiang Zhao ◽  
Liang Ding ◽  
Xihu Yang ◽  
...  
Keyword(s):  
Oxidative Phosphorylation ◽  
Mitochondrial Oxidative Phosphorylation ◽  
Metabolic Switch ◽  
Oxidative Phosphorylation System

scholarly journals Oxidative switch drives mitophagy defects in dopaminergic parkin mutant patient neurons

2020 ◽  
Author(s):  
Aurelie Schwartzentruber ◽  
Camilla Boschian ◽  
Fernanda Martins Lopes ◽  
Monika A Myszczynska ◽  
Elizabeth J New ◽  
...  
Keyword(s):  
Oxidative Phosphorylation ◽  
Progenitor Cells ◽  
Dopaminergic Neurons ◽  
Neuronal Morphology ◽  
Fluorescent Imaging ◽  
Mitochondrial Morphology ◽  
Metabolic Switch ◽  
Mitochondrial Abnormalities ◽  
Neuronal Progenitor Cells ◽  
Neuronal Progenitor

AbstractBackground Mutations in parkin are the most common cause of early onset Parkinson’s disease. Parkin is an E3 ubiquitin ligase, functioning in mitophagy. Mitochondrial abnormalities are present in parkin mutant models. Patient derived neurons are a promising model in which to study pathogenic mechanisms and therapeutic targets. Here we generate induced neuronal progenitor cells from parkin mutant patient fibroblasts with a high dopaminergic neuron yield. We reveal changing mitochondrial phenotypes as neurons undergo a metabolic switch during differentiation. Methods Fibroblasts from 4 controls and 4 parkin mutant patients were transformed into induced neuronal progenitor cells and subsequently differentiated into dopaminergic neurons. Mitochondrial morphology, function and mitophagy were evaluated using live cell fluorescent imaging, cellular ATP and reactive oxygen species production quantification. Results Direct conversion of control and parkin mutant patient fibroblasts results in induced neuronal progenitor and their differentiation yields high percentage of dopaminergic neurons. We were able to observe changing mitochondrial phenotypes as neurons undergo a metabolic switch during differentiation. Our results show that when pre-neurons are glycolytic early in differentiation mitophagy is unimpaired by PRKN deficiency. However as neurons become oxidative phosphorylation dependent, mitophagy is severely impaired in the PRKN mutant patient neurons. These changes correlate with changes in mitochondrial function and morphology; resulting in lower neuron yield and altered neuronal morphology. Conclusions Induced neuronal progenitor cell conversion can produce a high yield of dopaminergic neurons. The mitochondrial phenotype, including mitophagy status, is highly dependent on the metabolic status of the cell. Only when neurons are oxidative phosphorylation reliant the extent of mitochondrial abnormalities are identified. These data provide insight into cell specific effects of PRKN mutations, in particular in relation to mitophagy dependent disease phenotypes and provide avenues for alternative therapeutic approaches.

scholarly journals RNAase III-Type Enzyme Dicer Regulates Mitochondrial Fatty Acid Oxidative Metabolism in Cardiac Mesenchymal Stem Cells

2019 ◽  
Vol 20 (22) ◽  
pp. 5554 ◽  
Author(s):  
Xuan Su ◽  
Yue Jin ◽  
Yan Shen ◽  
Il-man Kim ◽  
Neal L. Weintraub ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Oxidative Phosphorylation ◽  
Oxidative Metabolism ◽  
Gene Deletion ◽  
Aerobic Glycolysis ◽  
Critical Role ◽  
Mitochondrial Oxidative Phosphorylation ◽  
Metabolic Switch ◽  
Mitochondrial Fatty Acid

Cardiac mesenchymal stem cells (C-MSC) play a key role in maintaining normal cardiac function under physiological and pathological conditions. Glycolysis and mitochondrial oxidative phosphorylation predominately account for energy production in C-MSC. Dicer, a ribonuclease III endoribonuclease, plays a critical role in the control of microRNA maturation in C-MSC, but its role in regulating C-MSC energy metabolism is largely unknown. In this study, we found that Dicer knockout led to concurrent increase in both cell proliferation and apoptosis in C-MSC compared to Dicer floxed C-MSC. We analyzed mitochondrial oxidative phosphorylation by quantifying cellular oxygen consumption rate (OCR), and glycolysis by quantifying the extracellular acidification rate (ECAR), in C-MSC with/without Dicer gene deletion. Dicer gene deletion significantly reduced mitochondrial oxidative phosphorylation while increasing glycolysis in C-MSC. Additionally, Dicer gene deletion selectively reduced the expression of β-oxidation genes without affecting the expression of genes involved in the tricarboxylic acid (TCA) cycle or electron transport chain (ETC). Finally, Dicer gene deletion reduced the copy number of mitochondrially encoded 1,4-Dihydronicotinamide adenine dinucleotide (NADH): ubiquinone oxidoreductase core subunit 6 (MT-ND6), a mitochondrial-encoded gene, in C-MSC. In conclusion, Dicer gene deletion induced a metabolic shift from oxidative metabolism to aerobic glycolysis in C-MSC, suggesting that Dicer functions as a metabolic switch in C-MSC, which in turn may regulate proliferation and environmental adaptation.

scholarly journals Iron regulatory protein 2 modulates the switch from aerobic glycolysis to oxidative phosphorylation in mouse embryonic fibroblasts

2019 ◽  
Vol 116 (20) ◽  
pp. 9871-9876 ◽  
Author(s):  
Huihui Li ◽  
Yutong Liu ◽  
Longcheng Shang ◽  
Jing Cai ◽  
Jing Wu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Oxidative Phosphorylation ◽  
Iron Homeostasis ◽  
Aerobic Glycolysis ◽  
Regulatory Protein ◽  
Specific Inhibitor ◽  
Mouse Embryonic Fibroblasts ◽  
Embryonic Fibroblasts ◽  
Metabolic Switch ◽  
Iron Regulatory Proteins

The importance of the role of iron regulatory proteins (IRPs) in mitochondrial iron homeostasis and function has been raised. To understand how an IRP affects mitochondrial function, we used globally Irp2-depleted mouse embryonic fibroblasts (MEFs) and found that Irp2 ablation significantly induced the expression of both hypoxia-inducible factor subunits, Hif1α and Hif2α. The increase of Hif1α up-regulated its targeted genes, enhancing glycolysis, and the increase of Hif2α down-regulated the expression of iron–sulfur cluster (Fe–S) biogenesis-related and electron transport chain (ETC)-related genes, weakening mitochondrial respiration. Inhibition of Hif1α by genetic knockdown or a specific inhibitor prevented Hif1α-targeted gene expression, leading to decreased aerobic glycolysis. Inhibition of Hif2α by genetic knockdown or selective disruption of the heterodimerization of Hif2α and Hif1β restored the mitochondrial ETC and coupled oxidative phosphorylation (OXPHOS) by enhancing Fe–S biogenesis and increasing ETC-related gene expression. Our results indicate that Irp2 modulates the metabolic switch from aerobic glycolysis to OXPHOS that is mediated by Hif1α and Hif2α in MEFs.

scholarly journals Potent Anticancer Effect of the Natural Steroidal Saponin Gracillin Is Produced by Inhibiting Glycolysis and Oxidative Phosphorylation-Mediated Bioenergetics

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 913 ◽  
Author(s):  
Hye-Young Min ◽  
Honglan Pei ◽  
Seung Yeob Hyun ◽  
Hye-Jin Boo ◽  
Hyun-Ji Jang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Oxidative Phosphorylation ◽  
Cancer Cells ◽  
Anticancer Agent ◽  
Aerobic Glycolysis ◽  
Cancer Cell Line ◽  
Steroidal Saponin ◽  
Antitumor Effects ◽  
Metabolic Switch ◽  
Atp Production

Metabolic rewiring to utilize aerobic glycolysis is a hallmark of cancer. However, recent findings suggest the role of mitochondria in energy generation in cancer cells and the metabolic switch to oxidative phosphorylation (OXPHOS) in response to the blockade of glycolysis. We previously demonstrated that the antitumor effect of gracillin occurs through the inhibition of mitochondrial complex II-mediated energy production. Here, we investigated the potential of gracillin as an anticancer agent targeting both glycolysis and OXPHOS in breast and lung cancer cells. Along with the reduction in adenosine triphosphate (ATP) production, gracillin markedly suppresses the production of several glycolysis-associated metabolites. A docking analysis and enzyme assay suggested phosphoglycerate kinase 1 (PGK1) is a potential target for the antiglycolytic effect of gracillin. Gracillin reduced the viability and colony formation ability of breast cancer cells by inducing apoptosis. Gracillin displayed efficacious antitumor effects in mice bearing breast cancer cell line or breast cancer patient-derived tumor xenografts with no overt changes in body weight. An analysis of publicly available datasets further suggested that PGK1 expression is associated with metastasis status and poor prognosis in patients with breast cancer. These results suggest that gracillin is a natural anticancer agent that inhibits both glycolysis and mitochondria-mediated bioenergetics.

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