STAT3 Modulates CD4+ T Mitochondrial Dynamics and Function in Aging
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE241492 | GEO | 2023/10/17
REPOSITORIES: GEO
Similar Datasets
Project description:Mitochondria control bioenergetics and cell fate decisions, but whether they also participate in extra-organelle signaling is not understood. Here, we show that interference with cyclophilin D (CypD), a mitochondrial matrix protein and apoptosis regulator, causes accelerated cell proliferation and enhanced cell migration and invasion. These responses are associated with global transcriptional changes in CypD-/- cells, predominantly affecting chemokines and their receptors, and resulting in increased activating phosphorylation of Signal Transduction and Activator of Transcription 3 (STAT3). In turn, STAT3 signaling promotes increased proliferation of CypD-/- cells via accelerated S-phase entry and supports Cxcl12-directed paracrine cell motility. Therefore, mitochondria-to-nuclei transcriptional signaling globally affects cell division and motility. As immunosuppressive therapies often target CypD, this pathway may predispose the tissue microenvironment of these patients to oncogenic transformation. Three wild type (WT) and three CypD-/- knock-out mouse embryonic fibroblasts (MEFs) have been compared.
2013-03-08 | E-GEOD-41280 | biostudies-arrayexpress
Project description:Abstract: Human kidney function declines with age, accompanied by stereotyped changes in gene expression and histopathology, but the mechanisms underlying these changes are largely unknown. We compared age-associated changes in global gene expression patterns in the human kidney with genome-wide maps of transcription factor occupancy in human cell lines to identify potential regulators of gene expression changes in the aging kidney. The strongest associations involved three inflammation-associated transcription factors: NFκB, STAT1 and STAT3. We found that the activity of these transcription factors increases with age in epithelial compartments of the renal cortex. Stimulation of renal tubular epithelial cells with the inflammatory cytokines IL-6 (a STAT3 activator), IFN-γ (a STAT1 activator), or TNFα (an NFκB activator) recapitulated age-associated gene expression changes. We found that common DNA variants in the two genes that encode the subunits of the canonical NFκB transcription factor (RELA and NFKB1) showed significant associations with kidney function and chronic kidney disease in gene association studies, providing the first evidence for a direct link between genetic variation in NFκB and individual differences in age-related phenotypes in the kidney. Our results point to chronic inflammation, mediated by NFκB, STAT1 and STAT3, as a dominant mechanism influencing gene expression changes during kidney aging. Biological triplicate experiments were performed for each cytokine treatment condition or control treatment.
2015-07-01 | E-GEOD-68940 | biostudies-arrayexpress
Project description:Abstract: Human kidney function declines with age, accompanied by stereotyped changes in gene expression and histopathology, but the mechanisms underlying these changes are largely unknown. We compared age-associated changes in global gene expression patterns in the human kidney with genome-wide maps of transcription factor occupancy in human cell lines to identify potential regulators of gene expression changes in the aging kidney. The strongest associations involved three inflammation-associated transcription factors: NFκB, STAT1 and STAT3. We found that the activity of these transcription factors increases with age in epithelial compartments of the renal cortex. Stimulation of renal tubular epithelial cells with the inflammatory cytokines IL-6 (a STAT3 activator), IFN-γ (a STAT1 activator), or TNFα (an NFκB activator) recapitulated age-associated gene expression changes. We found that common DNA variants in the two genes that encode the subunits of the canonical NFκB transcription factor (RELA and NFKB1) showed significant associations with kidney function and chronic kidney disease in gene association studies, providing the first evidence for a direct link between genetic variation in NFκB and individual differences in age-related phenotypes in the kidney. Our results point to chronic inflammation, mediated by NFκB, STAT1 and STAT3, as a dominant mechanism influencing gene expression changes during kidney aging. Biological triplicate experiments were performed for each cytokine treatment condition or control treatment.
2015-07-01 | E-GEOD-68941 | biostudies-arrayexpress
Project description:Abstract: Human kidney function declines with age, accompanied by stereotyped changes in gene expression and histopathology, but the mechanisms underlying these changes are largely unknown. We compared age-associated changes in global gene expression patterns in the human kidney with genome-wide maps of transcription factor occupancy in human cell lines to identify potential regulators of gene expression changes in the aging kidney. The strongest associations involved three inflammation-associated transcription factors: NFκB, STAT1 and STAT3. We found that the activity of these transcription factors increases with age in epithelial compartments of the renal cortex. Stimulation of renal tubular epithelial cells with the inflammatory cytokines IL-6 (a STAT3 activator), IFN-γ (a STAT1 activator), or TNFα (an NFκB activator) recapitulated age-associated gene expression changes. We found that common DNA variants in the two genes that encode the subunits of the canonical NFκB transcription factor (RELA and NFKB1) showed significant associations with kidney function and chronic kidney disease in gene association studies, providing the first evidence for a direct link between genetic variation in NFκB and individual differences in age-related phenotypes in the kidney. Our results point to chronic inflammation, mediated by NFκB, STAT1 and STAT3, as a dominant mechanism influencing gene expression changes during kidney aging. Biological duplicate or triplicate experiments were profiled for each cytokine treatment or control condition
2015-07-01 | E-GEOD-68942 | biostudies-arrayexpress
Project description:Caloric restriction (CR) without malnutrition appears to mitigate many detrimental effects of aging, in particular the age-related decline in skeletal muscle mitochondrial function. Although the mechanisms responsible for this protective effect remain unclear, CR is commonly believed to increase mitochondrial biogenesis; a concept that is now demanding closer scrutiny. Here we show that lifelong CR in mice prevents age-related loss of mitochondrial function, measured in isolated mitochondria and permeabilized muscle fibers. We find that these beneficial effects of CR occur without increasing mitochondrial abundance. Furthermore, whole-genome expression profiling and large-scale proteomic surveys revealed expression patterns inconsistent with increased mitochondrial biogenesis. These observations, combined with lower protein synthesis rates support an alternative hypothesis that CR preserves mitochondrial function not by increasing mitochondrial biogenesis, but rather by decreasing mitochondrial oxidant emission, increasing antioxidant scavenging, thereby minimizing oxidative damage to cellular components. Cross-sectional comparison of skeletal muscle from young (8mo), old (24mo) and old caloric restricted mice, obtained from the colony maintained on behalf of the National Institute on Aging.
2013-01-01 | E-GEOD-36285 | biostudies-arrayexpress
Project description:Aging is the progressive decline in organismal function that leads to an increased risk of multiple diseases and mortality. The molecular basis of this decline is unknown. Using quantitative PCR for mitochondrial mRNA from multiple tissues from the same animals, we found that the rate of change in mouse mitochondrial expression is tissue-specific, with cardiac expression declining early (8-10 months), adipose expression declining late (25-30 months), and no change in kidney or skin. In cardiac tissue, mitochondria-derived mRNA levels declined more slowly than nuclear encoded mRNAs, suggesting a potential dysregulation. These changes were independent of alteration in mitochondrial number, as measured by quantitative PCR of mitochondrial DNA and citrate synthase activity. We found no change in the variability between mitochondrial mRNA levels with age, suggesting that the changes are not due to random dysregulation at the level of gene expression. Caloric restriction (CR), a lifespan-extending intervention proposed to act through mitochondrial biogenesis, delayed the decline in both cardiac and adipose mitochondrial mRNA levels of F344 rats. CR caused an increase in citrate synthase activity but did not alter mitochondrial DNA content, indicating increased translation or reduced turnover of mitochondrial proteins. These results demonstrate that mitochondrial gene expression changes with age are not coupled to mitochondrial number, are likely to be regulated, and are governed by tissue-specific processes. These findings indicate that aging is neither a programmed organism-wide change orchestrated in a top-down fashion nor a product of random dysregulation of gene expression but that tissue-specific factors may independently control aging in different organ compartments. Keywords: aging Cardiac ventricle total RNA from 10 young (4-6 month) and 10 young (25-28 month) mice were compared.
2015-07-03 | E-GEOD-12480 | biostudies-arrayexpress
Project description:Metabolic reprogramming of mitochondria occurs during development, cell differentiation and in disease and is coupled to changes in mitochondrial mass and shape. Here, we demonstrate that the i-AAA protease YME1L rewires the proteome of pre-existing mitochondria in response to hypoxia or nutrient starvation. Inhibition of mTORC1 induces a lipid signalling cascade via the phosphatidic acid phosphatase LIPIN1, which decreases phosphatidylethanolamine levels in mitochondrial membranes and promotes proteolysis. YME1L degrades mitochondrial protein translocases, lipid transfer proteins and metabolic enzymes to acutely limit mitochondrial biogenesis and support cell growth. YME1L-mediated mitochondrial reshaping ensures spheroid and xenograft growth of pancreatic ductal adenocarcinoma (PDAC) cells. Similar mitochondrial proteome changes occur in tumour tissues of PDAC patients, suggesting that YME1L is relevant to the pathophysiology of specific solid tumours. Our results identify the mTORC1-LIPIN1-YME1L axis as a novel post-translational regulator of mitochondrial proteostasis at the interface of metabolism and mitochondrial dynamics.
2019-08-28 | GSE133753 | GEO
Project description:Mitochondria control bioenergetics and cell fate decisions, but whether they also participate in extra-organelle signaling is not understood. Here, we show that interference with cyclophilin D (CypD), a mitochondrial matrix protein and apoptosis regulator, causes accelerated cell proliferation and enhanced cell migration and invasion. These responses are associated with global transcriptional changes in CypD-/- cells, predominantly affecting chemokines and their receptors, and resulting in increased activating phosphorylation of Signal Transduction and Activator of Transcription 3 (STAT3). In turn, STAT3 signaling promotes increased proliferation of CypD-/- cells via accelerated S-phase entry and supports Cxcl12-directed paracrine cell motility. Therefore, mitochondria-to-nuclei transcriptional signaling globally affects cell division and motility. As immunosuppressive therapies often target CypD, this pathway may predispose the tissue microenvironment of these patients to oncogenic transformation.
2013-03-08 | GSE41280 | GEO
Project description:Functional decline and structural alterations of the brain microvasculature are associated with cognitive impairment and development of dementias such as Alzheimer’s disease during aging. Although mechanisms of leading to microvascular changes during aging are not clear, the loss of mitochondria and reduced efficiency of remaining mitochondria appear to play a major role. While pharmacological agents which target mitochondria such as SS-31 have been shown to be effective in beneficial during aging and diseases, the full extent on mitochondrial- and non-mitochondrial proteins in the brain microvasculature has not been examined. We tested the hypothesis that attenuation of aging-associated changes in the brain microvascular proteome via targeting mitochondria represents a therapeutic option in the aging brain. We used male, aged (>18 months) C57Bl6/J mice treated with a mitochondria-targeted tetrapeptide, SS-31 or vehicle saline. Baseline cerebral blood flow (CBF) was determined using laser speckle imaging during the two-week treatment period. Then, isolated cortical microvessels (MVs), composed of end arterioles, capillaries, and venules, were used for Orbitrap Eclipse Tribrid mass spectrometry. Baseline CBF was similar between the groups, whereas bioinformatic analysis revealed substantial differences in protein abundance of cortical MVs between SS-31 and vehicle groups. Specifically, we identified 6,266 proteins in our data set from which 12% were mitochondrial or mitochondria associated. 107 of these proteins were significantly differentially expressed between the treatment and vehicle groups, and were associated with the oxidative phosphorylation, metabolism, antioxidant defense system, or mitochondrial dynamics. Administration of SS-31 also affected many non-mitochondrial proteins. Our findings suggest that mitochondria in the microvasculature represent a therapeutic target in the aging brain, and widespread changes in the proteome may underlie the mechanisms of rejuvenating actions of SS-31 in the aging phenotype.
2024-01-26 | PXD038483 | Pride
Project description:Mitochondria are highly dynamic organelles undergoing fusion, fission and degradation. Although mitochondria are known to be essential for cellular metabolism, it is not fully understood how mitochondrial dynamics affect cellular metabolism. We previously identified a mouse gene, transmembrane protein 135 (TMEM135) that plays a role in the regulation of mitochondrial dynamics. Mice with mutant Tmem135 (Tmem135FUN025/FUN025) show accelerated aging phenotypes and age-related pathologies in the retina including the retinal pigment epithelium (RPE). We also generated a transgenic mouse line globally overexpressing the Tmem135 gene (Tmem135 TG). In several tissues and cells that we studied such as the retina, heart and fibroblast cells, we observed that the Tmem135 mutation causes elongated mitochondria, while over-expression of Tmem135 results in fragmented mitochondria. These unique mouse models allow us to test how abnormal mitochondrial dynamics affect metabolic signatures of tissues and cells. In this study, we identified metabolic changes in primary RPE cell cultures as well as tissues isolated from Tmem135FUN025/FUN025 mice (fusion > fission) and Tmem135 TG mice (fusion < fission) using nuclear magnetic resonance (NMR) spectroscopy. Metabolomics analysis revealed a tissue-dependent response to alterations to Tmem135 whereby, significant metabolic changes were observed in heart in both mutant and TG mice as compared to WT while negligible effects were observed in cerebellum and hippocampus. We also observed changes in Tmem135FUN025/FUN025 and Tmem135 TG RPE cells associated with osmosis, glucose metabolism and phospholipid metabolism. Significant depletion of NAD+ was detected in both Tmem135FUN025/FUN025 and Tmem135 TG RPE cells, indicating that imbalance in mitochondrial dynamics to both directions lowers the cellular NAD+ level. Thus, we have identified metabolomic changes associated with imbalanced mitochondrial dynamics in heart tissue and RPE cells which can likely lead to functional abnormalities.
2021-02-12 | MTBLS1410 | MetaboLights