Peroxisome Proliferator-activated Receptor γ (PPARγ) Mediates a Ski Oncogene-induced Shift from Glycolysis to Oxidative Energy Metabolism

Ye, Fang; Lemieux, Hélène; Hoppel, Charles L.; Hanson, Richard W.; Hakimi, Parvin; Croniger, Colleen M.; Puchowicz, Michelle A.; Anderson, Vernon E.; Fujioka, Hisashi; Stavnezer, Ed

doi:10.1074/jbc.m111.292029

Cited by 11 publications

(10 citation statements)

References 62 publications

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“…Although their roles are not well defined in birds, the NRF-1 and Ski play a key role in mammalian mitochondrial biogenesis and respiratory function (75,76). Mammalian NRF-1 is a direct target for PPAR␥ and PGC-1 (75).…”

Section: Discussionmentioning

confidence: 99%

Orexin system is expressed in avian muscle cells and regulates mitochondrial dynamics

Lassiter¹,

Greene²,

Piekarski³

et al. 2015

American Journal of Physiology-Regulatory, Integrative and Comp

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Orexin A and B, orexigenic peptides produced primarily by the lateral hypothalamus that signal through two G protein-coupled receptors, orexin receptors 1/2, have been implicated in the regulation of several physiological processes in mammals. In avian (nonmammalian vertebrates) species; however, the physiological roles of orexin are not well defined. Here, we provide novel evidence that not only is orexin and its related receptors 1/2 (ORXR1/2) expressed in chicken muscle tissue and quail muscle (QM7) cell line, orexin appears to be a secretory protein in QM7 cells. In vitro administration of recombinant orexin A and B (rORX-A and B) differentially regulated prepro-orexin expression in a dose-dependent manner with up-regulation for rORX-A (P < 0.05) and downregulation for rORX-B (P < 0.05) in QM7 cells. While both peptides upregulated ORXR1 expression, only a high dose of rORX-B decreased the expression of ORXR2 (P < 0.05). The presence of orexin and its related receptors and the regulation of its own system in avian muscle cells indicate that orexin may have autocrine, paracrine, and/or endocrine roles. rORXs differentially regulated mitochondrial dynamics network. While rORX-A significantly induced the expression of mitochondrial fission-related genes (DNM1, MTFP1, MTFR1), rORX-B increased the expression of mitofusin 2, OPA1, and OMA1 genes that are involved in mitochondrial fusion. Concomitant with these changes, rORXs differentially regulated the expression of several mitochondrial metabolic genes (av-UCP, av-ANT, Ski, and NRF-1) and their related transcriptional regulators (PPARγ, PPARα, PGC-1α, PGC-1β, and FoxO-1) without affecting ATP synthesis. Taken together, our data represent the first evidence of the presence and secretion of orexin system in the muscle of nonmammalian species and its role in mitochondrial fusion and fission, probably through mitochondrial-related genes and their related transcription factors.

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Section: Discussionmentioning

confidence: 99%

Orexin system is expressed in avian muscle cells and regulates mitochondrial dynamics

Lassiter¹,

Greene²,

Piekarski³

et al. 2015

American Journal of Physiology-Regulatory, Integrative and Comp

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“…Cellular aerobic respiration was measured using high-resolution respirometry (Oxygraph-2k, Oroboros Instruments, Innsbruck, Austria) [23], as we have performed before [24]. In brief, the oxygraph was calibrated at 37 • C per the manufacturer's instructions with each chamber filled with 2 mL of mitochondrial respiration medium 05 (MIR05) containing 110 mM sucrose, 60 mM K-lactobionate, 0.5 mM EGTA, 0.1% BSA, 3 mM MgCl 2 , 20 mM taurine, 10 mM KH 2 PO 4 , and 20 mM HEPES [25], which was magnetically stirred at 500 rpm.…”

Section: High-resolution Respirometrymentioning

confidence: 99%

Disruption of Beta-Cell Mitochondrial Networks by the Orphan Nuclear Receptor Nor1/Nr4a3

Dadheech

Lemieux

et al. 2020

Cells

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Nor1, the third member of the Nr4a subfamily of nuclear receptor, is garnering increased interest in view of its role in the regulation of glucose homeostasis. Our previous study highlighted a proapoptotic role of Nor1 in pancreatic beta cells and showed that Nor1 expression was increased in islets isolated from type 2 diabetic individuals, suggesting that Nor1 could mediate the deterioration of islet function in type 2 diabetes. However, the mechanism remains incompletely understood. We herein investigated the subcellular localization of Nor1 in INS832/13 cells and dispersed human beta cells. We also examined the consequences of Nor1 overexpression on mitochondrial function and morphology. Our results show that, surprisingly, Nor1 is mostly cytoplasmic in beta cells and undergoes mitochondrial translocation upon activation by proinflammatory cytokines. Mitochondrial localization of Nor1 reduced glucose oxidation, lowered ATP production rates, and inhibited glucose-stimulated insulin secretion. Western blot and microscopy images revealed that Nor1 could provoke mitochondrial fragmentation via mitophagy. Our study unveils a new mode of action for Nor1, which affects beta-cell viability and function by disrupting mitochondrial networks.

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“…Sorted cells were pelleted and fixed with 2.5% glutaraldehyde, and then embedded as previously described [47]. Standard transmission electron microscopy ultrastructural analysis was performed at Electron Microscopy Facility of CWRU.…”

Section: Electron Microscopymentioning

confidence: 99%

Cited2 Is Required for the Maintenance of Glycolytic Metabolism in Adult Hematopoietic Stem Cells

Tang

et al. 2014

Stem Cells and Development

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Mammalian adult hematopoietic stem cells (HSCs) reside in the hypoxic bone marrow microenvironment and display a distinct metabolic phenotype compared with their progenitors. It has been proposed that HSCs generate energy mainly through anaerobic glycolysis in a pyruvate dehydrogenase kinase (Pdk)-dependent manner. Cited2 is an essential regulator for HSC quiescence, apoptosis, and function. Herein, we show that conditional deletion of Cited2 in murine HSCs results in elevated levels of reactive oxygen species, decreased cellular glutathione content, increased mitochondrial activity, and decreased glycolysis. At the molecular level, Cited2 deficiency significantly reduced the expression of genes involved in metabolism, such as Pdk2, Pdk4, and lactate dehydrogenases B and D (LDHB and LDHD). Cited2-deficient HSCs also exhibited increased Akt signaling, concomitant with elevated mTORC1 activity and phosphorylation of FoxOs. Further, inhibition of PI3/Akt, but not mTORC1, partially rescued the repression of Pdk4 caused by deletion of Cited2. Altogether, our results suggest that Cited2 is required for the maintenance of adult HSC glycolytic metabolism likely through regulating Pdk2, Pdk4, LDHB, LDHD, and Akt activity.

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Peroxisome Proliferator-activated Receptor γ (PPARγ) Mediates a Ski Oncogene-induced Shift from Glycolysis to Oxidative Energy Metabolism

Cited by 11 publications

References 62 publications

Orexin system is expressed in avian muscle cells and regulates mitochondrial dynamics

Orexin system is expressed in avian muscle cells and regulates mitochondrial dynamics

Disruption of Beta-Cell Mitochondrial Networks by the Orphan Nuclear Receptor Nor1/Nr4a3

Cited2 Is Required for the Maintenance of Glycolytic Metabolism in Adult Hematopoietic Stem Cells

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