STAT3 regulates mitochondrial gene expression in pancreatic β-cells and its deficiency induces glucose intolerance in obesity

Diabetes ◽  
2021 ◽  
pp. db201222
Author(s):  
Anaïs Schaschkow ◽  
Lokman Pang ◽  
Valerie Vandenbempt ◽  
Bernat Elvira ◽  
Sara A. Litwak ◽  
...  
Keyword(s):  
Gene Expression ◽  
Glucose Intolerance ◽  
Mitochondrial Gene ◽  
Mitochondrial Gene Expression ◽  
Β Cells ◽  
Pancreatic Β Cells

scholarly journals STAT3 Regulates Mitochondrial Gene Expression in Pancreatic β-Cells and its Deficiency Induces Glucose Intolerance in Obesity

2021 ◽  
Author(s):  
Anaïs Schaschkow ◽  
Lokman Pang ◽  
Valerie Vandenbempt ◽  
Bernat Elvira ◽  
Sara A. Litwak ◽  
...  
Keyword(s):  
Gene Expression ◽  
Glucose Intolerance ◽  
High Fat Diet ◽  
Cell Function ◽  
Mitochondrial Gene ◽  
High Fat ◽  
Β Cells ◽  
Β Cell ◽  
Β Cell Function ◽  
Deficient Mice

Most obese and insulin-resistant individuals do not develop diabetes. This is the result of the capacity of β-cells to adapt and produce enough insulin to cover the needs of the organism. The underlying mechanism of β-cell adaptation in obesity, however, remains unclear. Previous studies have suggested a role for STAT3 in mediating β-cell development and human glucose homeostasis, but little is known about STAT3 in β-cells in obesity. We observed enhanced cytoplasmic expression of STAT3 in severely obese and diabetic subjects. To address the functional role of STAT3 in adult β-cells, we generated mice with tamoxifen-inducible partial or full deletion of STAT3 in β-cells and fed them a high-fat diet before analysis. Interestingly, β-cell heterozygous and homozygous STAT3-deficient mice showed glucose intolerance when fed a high-fat diet. Gene expression analysis by RNA-Seq showed reduced expression of mitochondrial genes in STAT3 knocked down human EndoC-βH1 cells and was confirmed in FACS-purified β-cells from obese STAT3-deficient mice. Moreover, silencing of STAT3 impaired mitochondria activity in EndoC-βH1 cells and human islets, suggesting a mechanism for STAT3-modulated β-cell function. We propose STAT3 as a regulator of β-cell function, improving glucose-induced insulin secretion in obesity.

scholarly journals STAT3 Regulates Mitochondrial Gene Expression in Pancreatic β-Cells and its Deficiency Induces Glucose Intolerance in Obesity

2021 ◽  
Author(s):  
Anaïs Schaschkow ◽  
Lokman Pang ◽  
Valerie Vandenbempt ◽  
Bernat Elvira ◽  
Sara A. Litwak ◽  
...  
Keyword(s):  
Gene Expression ◽  
Glucose Intolerance ◽  
High Fat Diet ◽  
Cell Function ◽  
Mitochondrial Gene ◽  
High Fat ◽  
Β Cells ◽  
Β Cell ◽  
Β Cell Function ◽  
Deficient Mice

Most obese and insulin-resistant individuals do not develop diabetes. This is the result of the capacity of β-cells to adapt and produce enough insulin to cover the needs of the organism. The underlying mechanism of β-cell adaptation in obesity, however, remains unclear. Previous studies have suggested a role for STAT3 in mediating β-cell development and human glucose homeostasis, but little is known about STAT3 in β-cells in obesity. We observed enhanced cytoplasmic expression of STAT3 in severely obese and diabetic subjects. To address the functional role of STAT3 in adult β-cells, we generated mice with tamoxifen-inducible partial or full deletion of STAT3 in β-cells and fed them a high-fat diet before analysis. Interestingly, β-cell heterozygous and homozygous STAT3-deficient mice showed glucose intolerance when fed a high-fat diet. Gene expression analysis by RNA-Seq showed reduced expression of mitochondrial genes in STAT3 knocked down human EndoC-βH1 cells and was confirmed in FACS-purified β-cells from obese STAT3-deficient mice. Moreover, silencing of STAT3 impaired mitochondria activity in EndoC-βH1 cells and human islets, suggesting a mechanism for STAT3-modulated β-cell function. We propose STAT3 as a regulator of β-cell function, improving glucose-induced insulin secretion in obesity.

scholarly journals Mitochondrial Glucocorticoid Receptors and Their Actions

2021 ◽  
Vol 22 (11) ◽  
pp. 6054
Author(s):  
Ioanna Kokkinopoulou ◽  
Paraskevi Moutsatsou
Keyword(s):  
Gene Expression ◽  
Glucocorticoid Receptors ◽  
Mitochondrial Gene ◽  
Cell Types ◽  
Ros Generation ◽  
Mitochondrial Gene Expression ◽  
Mitochondrial Energy Metabolism ◽  
Bcl2 Family ◽  
Cellular Processes ◽  
Almost All

Mitochondria are membrane organelles present in almost all eukaryotic cells. In addition to their well-known role in energy production, mitochondria regulate central cellular processes, including calcium homeostasis, Reactive Oxygen Species (ROS) generation, cell death, thermogenesis, and biosynthesis of lipids, nucleic acids, and steroid hormones. Glucocorticoids (GCs) regulate the mitochondrially encoded oxidative phosphorylation gene expression and mitochondrial energy metabolism. The identification of Glucocorticoid Response Elements (GREs) in mitochondrial sequences and the detection of Glucocorticoid Receptor (GR) in mitochondria of different cell types gave support to hypothesis that mitochondrial GR directly regulates mitochondrial gene expression. Numerous studies have revealed changes in mitochondrial gene expression alongside with GR import/export in mitochondria, confirming the direct effects of GCs on mitochondrial genome. Further evidence has made clear that mitochondrial GR is involved in mitochondrial function and apoptosis-mediated processes, through interacting or altering the distribution of Bcl2 family members. Even though its exact translocation mechanisms remain unknown, data have shown that GR chaperones (Hsp70/90, Bag-1, FKBP51), the anti-apoptotic protein Bcl-2, the HDAC6- mediated deacetylation and the outer mitochondrial translocation complexes (Tom complexes) co-ordinate GR mitochondrial trafficking. A role of mitochondrial GR in stress and depression as well as in lung and hepatic inflammation has also been demonstrated.

scholarly journals Mitochondrial Mistranslation in Brain Provokes a Metabolic Response Which Mitigates the Age-Associated Decline in Mitochondrial Gene Expression

2021 ◽  
Vol 22 (5) ◽  
pp. 2746
Author(s):  
Dimitri Shcherbakov ◽  
Reda Juskeviciene ◽  
Adrián Cortés Sanchón ◽  
Margarita Brilkova ◽  
Hubert Rehrauer ◽  
...  
Keyword(s):  
Gene Expression ◽  
Metabolic Response ◽  
Mitochondrial Gene ◽  
Tca Cycle ◽  
Brain Mitochondria ◽  
Mitochondrial Gene Expression ◽  
Rna Seq ◽  
The Tca Cycle ◽  
Neurological Phenotype

Mitochondrial misreading, conferred by mutation V338Y in mitoribosomal protein Mrps5, in-vivo is associated with a subtle neurological phenotype. Brain mitochondria of homozygous knock-in mutant Mrps5V338Y/V338Y mice show decreased oxygen consumption and reduced ATP levels. Using a combination of unbiased RNA-Seq with untargeted metabolomics, we here demonstrate a concerted response, which alleviates the impaired functionality of OXPHOS complexes in Mrps5 mutant mice. This concerted response mitigates the age-associated decline in mitochondrial gene expression and compensates for impaired respiration by transcriptional upregulation of OXPHOS components together with anaplerotic replenishment of the TCA cycle (pyruvate, 2-ketoglutarate).

scholarly journals Regulation of nuclear and mitochondrial gene expression by contractile activity in skeletal muscle.

1986 ◽  
Vol 261 (1) ◽  
pp. 376-380 ◽  
Author(s):  
R S Williams ◽  
S Salmons ◽  
E A Newsholme ◽  
R E Kaufman ◽  
J Mellor
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Contractile Activity ◽  
Mitochondrial Gene ◽  
Mitochondrial Gene Expression

scholarly journals Quantitative proteomics revealed C6orf203/MTRES1 as a factor preventing stress-induced transcription deficiency in human mitochondria

2019 ◽  
Vol 47 (14) ◽  
pp. 7502-7517 ◽  
Author(s):  
Anna V Kotrys ◽  
Dominik Cysewski ◽  
Sylwia D Czarnomska ◽  
Zbigniew Pietras ◽  
Lukasz S Borowski ◽  
...  
Keyword(s):  
Gene Expression ◽  
Rna Binding ◽  
Mitochondrial Gene ◽  
Binding Activity ◽  
Stress Conditions ◽  
Mitochondrial Rna ◽  
Mitochondrial Gene Expression ◽  
Compensatory Mechanisms ◽  
Temporary Reduction ◽  
Mitochondrial Transcription

AbstractMaintenance of mitochondrial gene expression is crucial for cellular homeostasis. Stress conditions may lead to a temporary reduction of mitochondrial genome copy number, raising the risk of insufficient expression of mitochondrial encoded genes. Little is known how compensatory mechanisms operate to maintain proper mitochondrial transcripts levels upon disturbed transcription and which proteins are involved in them. Here we performed a quantitative proteomic screen to search for proteins that sustain expression of mtDNA under stress conditions. Analysis of stress-induced changes of the human mitochondrial proteome led to the identification of several proteins with poorly defined functions among which we focused on C6orf203, which we named MTRES1 (Mitochondrial Transcription Rescue Factor 1). We found that the level of MTRES1 is elevated in cells under stress and we show that this upregulation of MTRES1 prevents mitochondrial transcript loss under perturbed mitochondrial gene expression. This protective effect depends on the RNA binding activity of MTRES1. Functional analysis revealed that MTRES1 associates with mitochondrial RNA polymerase POLRMT and acts by increasing mitochondrial transcription, without changing the stability of mitochondrial RNAs. We propose that MTRES1 is an example of a protein that protects the cell from mitochondrial RNA loss during stress.

Adipocyte differentiation, mitochondrial gene expression and fat distribution: differences between zidovudine and tenofovir after 6 months

2009 ◽  
Vol 14 (8) ◽  
pp. 1089-1100 ◽  
Author(s):  
Meg Boothby ◽  
Kirsty C McGee ◽  
Jeremy W Tomlinson ◽  
Laura L Gathercole ◽  
Philip G McTernan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Adipocyte Differentiation ◽  
Mitochondrial Gene ◽  
Fat Distribution ◽  
Mitochondrial Gene Expression

scholarly journals Mitochondrial Cyclic AMP Response Element-binding Protein (CREB) Mediates Mitochondrial Gene Expression and Neuronal Survival

2005 ◽  
Vol 280 (49) ◽  
pp. 40398-40401 ◽  
Author(s):  
Junghee Lee ◽  
Chun-Hyung Kim ◽  
David K. Simon ◽  
Lyaylya R. Aminova ◽  
Alexander Y. Andreyev ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cyclic Amp ◽  
Neuronal Survival ◽  
Binding Protein ◽  
Mitochondrial Gene ◽  
Mitochondrial Gene Expression ◽  
Response Element ◽  
Element Binding Protein ◽  
Cyclic Amp Response Element
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