PGC-1α regulates the mitochondrial antioxidant defense system in vascular endothelial cells

Valle, Inmaculada; Alvarez-Barrientos, Alberto; Arza, Elvira; Lamas, Santiago; Monsalve, Marı́a

doi:10.1016/j.cardiores.2005.01.026

Cited by 504 publications

(466 citation statements)

References 49 publications

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“…One possibility may involve the ability of PGC-1α, under some conditions, to activate genes that are implicated in the response to oxidative stress (34)(35)(36) and thus lead to a reduction of cellular oxidative stress levels. PGC-1α therefore may orchestrate the timely repression of HSPs in response to lower levels of oxidative stress.…”

Section: Discussionmentioning

confidence: 99%

Direct link between metabolic regulation and the heat-shock response through the transcriptional regulator PGC-1α

Minsky

Roeder

2015

Proc. Natl. Acad. Sci. U.S.A.

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In recent years an extensive effort has been made to elucidate the molecular pathways involved in metabolic signaling in health and disease. Here we show, surprisingly, that metabolic regulation and the heat-shock/stress response are directly linked. Peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), a critical transcriptional coactivator of metabolic genes, acts as a direct transcriptional repressor of heat-shock factor 1 (HSF1), a key regulator of the heat-shock/stress response. Our findings reveal that heatshock protein (HSP) gene expression is suppressed during fasting in mouse liver and in primary hepatocytes dependent on PGC-1α. HSF1 and PGC-1α associate physically and are colocalized on several HSP promoters. These observations are extended to several cancer cell lines in which PGC-1α is shown to repress the ability of HSF1 to activate gene-expression programs necessary for cancer survival. Our study reveals a surprising direct link between two major cellular transcriptional networks, highlighting a previously unrecognized facet of the activity of the central metabolic regulator PGC-1α beyond its well-established ability to boost metabolic genes via its interactions with nuclear hormone receptors and nuclear respiratory factors. Our data point to PGC-1α as a critical repressor of HSF1-mediated transcriptional programs, a finding with possible implications both for our understanding of the full scope of metabolically regulated target genes in vivo and, conceivably, for therapeutics. metabolism | transcription | stress response

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Section: Discussionmentioning

confidence: 99%

Direct link between metabolic regulation and the heat-shock response through the transcriptional regulator PGC-1α

Minsky

Roeder

2015

Proc. Natl. Acad. Sci. U.S.A.

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“…ROS production is proportional to the increase in mitochondrial respiration and electron transport chain activity (39). However, using muscle cells, it has been shown that PGC1α increases the expression of one of the major antioxidant enzymes of mitochondria, SOD2 (40)(41)(42). PGC1α is therefore able to upgrade aerobic energy metabolism while preserving ROS homeostasis by promoting ROS formation on one hand and ROS scavenging systems on the other.…”

Section: Discussionmentioning

confidence: 99%

Peroxisome proliferator-activated receptor-γ coactivator 1-α (PGC1α) is a metabolic regulator of intestinal epithelial cell fate

D'Errico

Salvatore

Murzilli

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

145

120

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Peroxisome proliferator-activated receptor-γ coactivator 1-α (PGC1α) is a transcriptional coactivator able to up-regulate mitochondrial biogenesis, respiratory capacity, oxidative phosphorylation, and fatty acid β-oxidation with the final aim of providing a more efficient pathway for aerobic energy production. In the continuously renewed intestinal epithelium, proliferative cells in the crypts migrate along the villus axis and differentiate into mature enterocytes, increasing their respiratory capacity and finally undergoing apoptosis. Here we show that in the intestinal epithelial surface, PGC1α drives mitochondrial biogenesis and respiration in the presence of reduced antioxidant enzyme activities, thus determining the accumulation of reactive oxygen species and fostering the fate of enterocytes toward apoptosis. Combining gain-and loss-offunction genetic approaches in human cells and mouse models of intestinal cancer, we present an intriguing scenario whereby PGC1α regulates enterocyte cell fate and protects against tumorigenesis.colon cancer | medical physiology | metabolism | mitochondria | nuclear receptors

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“…PGC-1α has been shown to be a master regulator of mitochondrial biogenesis and cellular energy [43] , and powerfully suppresses reactive oxygen species (ROS) in vivo [32] . Furthermore, PGC-1α knockout mice are much more sensitive to damage by oxidative stress, displaying apoptotic cell death in the dopaminergic cells of the substantia nigra and in hippocampal neurons [32] .…”

Section: Discussionmentioning

confidence: 99%

Asiatic acid, a pentacyclic triterpene in Centella asiatica, attenuates glutamate-induced cognitive deficits in mice and apoptosis in SH-SY5Y cells

et al. 2012

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Aim: To investigate whether asiatic acid (AA), a pentacyclic triterpene in Centella asiatica, exerted neuroprotective effects in vitro and in vivo, and to determine the underlying mechanisms. Methods: human neuroblastoma Sh-SY5Y cells were used for in vitro study. Cell viability was determined with the MTT assay. hoechst 33342 staining and flow cytometry were used to examine the apoptosis. The mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) were measured using fluorescent dye. PGC-1α and Sirt1 levels were examined using Western blotting. Neonatal mice were given monosodium glutamate (2.5 mg/g) subcutaneously at the neck from postnatal day (PD) 7 to 13, and orally administered with AA on PD 14 daily for 30 d. The learning and memory of the mice were evaluated with the Morris water maze test. hE staining was used to analyze the pyramidal layer structure in the CA1 and CA3 regions. Results: Pretreatment of Sh-SY5Y cells with AA (0.1-100 nmol/L) attenuated toxicity induced by 10 mmol/L glutamate in a concentration-dependent manner. AA 10 nmol/L significantly decreased apoptotic cell death and reduced reactive oxygen species (ROS), stabilized the mitochondrial membrane potential (MMP), and promoted the expression of PGC-1α and Sirt1. In the mice models, oral administration of AA (100 mg/kg) significantly attenuated cognitive deficits in the Morris water maze test, and restored lipid peroxidation and glutathione and the activity of SOD in the hippocampus and cortex to the control levels. AA (50 and 100 mg/kg) also attenuated neuronal damage of the pyramidal layer in the CA1 and CA3 regions. Conclusion: AA attenuates glutamate-induced cognitive deficits of mice and protects SH-SY5Y cells against glutamate-induced apoptosis in vitro.

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PGC-1α regulates the mitochondrial antioxidant defense system in vascular endothelial cells

Cited by 504 publications

References 49 publications

Direct link between metabolic regulation and the heat-shock response through the transcriptional regulator PGC-1α

Direct link between metabolic regulation and the heat-shock response through the transcriptional regulator PGC-1α

Peroxisome proliferator-activated receptor-γ coactivator 1-α (PGC1α) is a metabolic regulator of intestinal epithelial cell fate

Asiatic acid, a pentacyclic triterpene in Centella asiatica, attenuates glutamate-induced cognitive deficits in mice and apoptosis in SH-SY5Y cells

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