Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA238579 | ENA |
REPOSITORIES: ENA
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Project description:Extrinsic skin ageing converges on the dermis, a post-mitotic tissue compartment consisting of extracellular matrix and long-lived fibroblasts prone to damage accumulation and maladaptation. Aged human fibroblasts exhibit mitochondrial and nuclear dysfunctions, which may be a cause or consequence of ageing. We report on a systematic study of human dermal fibroblasts retrieved from female donors aged 20-67years and analysed ex vivo at low population doubling precluding replicative senescence. According to gene set enrichment analysis of genome wide array data, the most prominent age-associated change of the transcriptome was decreased expression of mitochondrial genes. Consistent with that, mitochondrial content and cell proliferation declined with donor age. This was associated with upregulation of AMP-dependent protein kinase (AMPK), increased mRNA levels of PPARγ-coactivator 1α (PGC1A) and decreased levels of NAD(+)-dependent deacetylase sirtuin 1. In the old cells the PGC1A-mediated mito-biogenetic response to direct AMPK-stimulation by AICAR was undiminished, while the PGC1A-independent mito-biogenetic response to starvation was attenuated and accompanied by increased ROS-production. In summary, these observations suggest an age-associated decline in PGC1A-independent mito-biogenesis, which is insufficiently compensated by upregulation of the AMPK/PGC1A-axis leading under baseline conditions to decreased mitochondrial content and reductive overload of residual respiratory capacity.
2014-04-08 | GSE55118 | GEO
Project description:Extrinsic skin ageing converges on the dermis, a post-mitotic tissue compartment consisting of extracellular matrix and long-lived fibroblasts prone to damage accumulation and maladaptation. Aged human fibroblasts exhibit mitochondrial and nuclear dysfunctions, but it is unclear whether these are cause or consequence of ageing. We report on a systematic study of human dermal fibroblasts retrieved from female donors aged 20-67 years and analyzed in primary culture at low population doubling precluding replicative senescence. Genome-wide array analysis failed to detect significant (>2-fold) age-related expression changes for individual genes, but gene set enrichment analysis revealed down regulation of many genes involved in mitochondrial metabolism and respiratory electron transport, extracellular matrix maintenance, cell cycle progression and protein translation. Consistent with these changes, mitochondrial content, respiratory function and cell proliferation declined with donor age. This was associated with inadequate nuclear mito-biogenesis, hypo- phosphorylation of AMP-dependent protein kinase alpha and upregulation of the alpha2-isoform, suggesting that inadequate mito-nuclear signalling could be the leading event entailing decreased expression of mitochondrial genes and compensatory down regulation of proliferation and protein synthesis. The comparatively few genes exhibiting age-associated up regulation were associate with cholesterol metabolism, immune reactions and mRNA processing, possibly also reflecting adaptation to inadequate mitochondrial function. Donors: 15 human female donors included in the study were aged 20, 21, 23, 26, 26, 40, 41, 42, 43, 49, 60, 62, 63, 64 and 67 years, thus covering the age spectrum 20 – 67 years and providing five biological replicates for each of the age groups “young” (20-30 years), “middle” (40-50 years) and “old” (60-70 years). Human dermal fibroblasts were isolated from skin specimen removed in the course of cosmetic surgery from the bottom side of female breast. Isolation and primary culture of the cells followed published procedures (Tigges and others 2013). Cells were not expanded beyond 12 population doublings, while replicative cell cycle arrest was determined to not occur before 40 population doublings.
2014-04-08 | E-GEOD-55118 | biostudies-arrayexpress
Project description:Mitochondria play a vital role in non-shivering thermogenesis in both brown and subcutaneous white adipose tissues (BAT and scWAT, respectively). However, specific regulatory mechanisms driving mitochondrial function in these tissues have been unclear. Here we demonstrate that prolonged activation of β-adrenergic signaling induces epigenetic modifications in scWAT, specifically targeting the enhancers for the mitochondria master regulator genes Pgc1a/b. This is mediated at least partially through JMJD1A, a histone demethylase that in response to β-adrenergic signals, facilitates H3K9 demethylation of the Pgc1a/b enhancers, promoting mitochondrial biogenesis and the formation of beige adipocytes. Disruption of demethylation activity of JMJD1A in mice impairs activation of Pgc1a/b driven mitochondrial biogenesis and limits scWAT beiging, contributing to reduced energy expenditure, obesity, insulin resistance, and metabolic disorders. Notably, JMJD1A demethylase activity is not required for Pgc1a/b dependent thermogenic capacity of BAT especially during acute cold stress, emphasizing the importance of scWAT thermogenesis in overall energy metabolism.
2024-03-12 | GSE236733 | GEO
Project description:Mitochondria play a vital role in non-shivering thermogenesis in both brown and subcutaneous white adipose tissues (BAT and scWAT, respectively). However, specific regulatory mechanisms driving mitochondrial function in these tissues have been unclear. Here we demonstrate that prolonged activation of β-adrenergic signaling induces epigenetic modifications in scWAT, specifically targeting the enhancers for the mitochondria master regulator genes Pgc1a/b. This is mediated at least partially through JMJD1A, a histone demethylase that in response to β-adrenergic signals, facilitates H3K9 demethylation of the Pgc1a/b enhancers, promoting mitochondrial biogenesis and the formation of beige adipocytes. Disruption of demethylation activity of JMJD1A in mice impairs activation of Pgc1a/b driven mitochondrial biogenesis and limits scWAT beiging, contributing to reduced energy expenditure, obesity, insulin resistance, and metabolic disorders. Notably, JMJD1A demethylase activity is not required for Pgc1a/b dependent thermogenic capacity of BAT especially during acute cold stress, emphasizing the importance of scWAT thermogenesis in overall energy metabolism.
2024-03-12 | GSE236724 | GEO
Project description:To assess transcriptomic changes that occur upon mito-tRNA Asparagine inhibition, MDA-MB-231 cells were transfected with either a non-targeting control locked nucleic acid (LNA), two independent LNAs targeting mito-tRNA Asparagine, or an LNA against mito-tRNA Lysine.
2023-07-01 | GSE213171 | GEO
Project description:We report the HDAC inhibiton of glioblastoma cells causes histone H3K27 acetylation and leads to upreguated OXPHOS master regulator PGC1a which then leads to an increase in mitochondrial fusion, mitochondrial biogenesis and higher mitochondrial oxygen consumption rate coupled with increased fatty acid oxidation (FAO).
2020-03-24 | GSE124877 | GEO
Project description:Because injured mitochondria can accelerate cell death through the elaboration of oxidative free radicals and other mediators, it is somewhat paradoxical that proliferator gamma coactivator 1-alpha (PGC1a), a stimulator of increased mitochondrial abundance, protects stressed renal cells instead of potentiating injury. Here we report that PGC1a’s induction of lysosomes via transcription factor EB (TFEB) may be pivotal for kidney protection. CRISPR and stable gene transfer showed that PGC1a knockout tubular cells were sensitized to the genotoxic stressor cisplatin whereas transgenic cells were protected. The biosensor mtKeima unexpectedly revealed that cisplatin blunts mitophagy both in cells and mice. PGC1a not only counteracted this effect but also raised basal mitophagy, as did the downstream mediator nicotinamide adenine dinucleotide (NAD+). PGC1a did not consistent affect known autophagy pathways modulated by cisplatin. Instead RNA sequencing identified coordinated regulation of lysosomal biogenesis via TFEB. This effector pathway was sufficiently important that inhibition of TFEB or lysosomes unveiled a striking harmful effect of excess PGC1a in cells and conditional mice. These results uncover an unexpected effect of cisplatin on mitophagy and PGC1a’s exquisite reliance on lysosomes for kidney protection. Finally, the data illuminate TFEB as a novel target for renal tubular stress resistance.
2019-06-10 | GSE126259 | GEO
Project description:Dermal invasion is a hallmark of malignant melanoma. The molecular alterations driving the progression of primary melanoma to metastatic disease have been studied extensively, whereas the early progression of non-invasive primary melanoma to an invasive state is not well understood. To elucidate the mechanisms underlying the transition from radial to vertical growth, the first step in melanoma invasion, we developed a zebrafish melanoma model in which constitutive activation of ribosomal protein S6 kinase 1 (RSK1) drives tumor invasion. Transcriptomic analysis of RSK1-activated tumors identified metabolic changes, including upregulation of genes associated with oxidative phosphorylation. Vertical growth phase human melanoma cells show higher oxygen consumption and preferential utilization of glutamine compared to radial growth phase melanoma cells. Peroxisome proliferator-activated receptor gamma coactivator-1α (PGC1a has been proposed as a master regulator of tumor oxidative phosphorylation. In human primary melanoma specimens we show that PGC1a protein expression is positively associated with increased tumor thickness and expression of the proliferative marker Ki-67 and the reactive oxygen species (ROS) scavenger SCARA3. PGC1a depletion modulates cellular processes associated with primary melanoma growth and invasion, including oxidative stress. Our results support a role for PGC1a in mediating glutamine-driven OXPHOS to facilitate the invasive growth of primary melanoma.
2020-01-24 | GSE144117 | GEO
Project description:Inadequate protein intake affects skeletal muscle transcript profiles in older humans
| PRJNA101511 | ENA