CASKIN1 Triggers Granulosa Cell Apoptosis via FOXO1-Mediated Mitochondrial Dysfunction
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus Musculus
SUBMITTER: 
Shunran Zhao
PROVIDER: PXD073151 | iProX | Fri Jan 16 00:00:00 GMT 2026
REPOSITORIES: iProX
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Project description:The mechanisms of oocyte meiotic defects and low competence during ovarian aging remains elusive for decades. Using Hi-C (genome-wide chromatin conformation capture) and Smart RNA-seq of oocytes from 6- weeks or 10- months aged ovaries, the abnormal loose chromatin structures and disturbing expression of meiosis associated genes at metaphase I phase were disclosed. Furthermore, the transcriptomic landscape of granulosa cells (GCs) surrounding oocytes from young and aged ovaries reveled that oocyte meiotic maturation was accompanied with a robust increased expression of genes involved with the mevalonate (MVA) pathway in GCs from young ovaries but these genes expression was not upregulated to counterpart level in GCs from aged ovaries.The inhibitor of MVA pathway of GCs, Statins significantly decreased polar body extrusion rate and increased the rate of irregularly assembled spindles and misaligned chromosomes remarkably in oocytes of culumus-oocyte complex (COCs) from young ovaries . Correspondingly, the activitor of MVA pathway of GCs, Geranylgeraniol ameliorated ovarian reserve and reduced meiotic defects in oocytes of COCs from aged ovaries. Mechanistically, MVA pathway activation in GCs culminated oocyte meiotic maturation by upregulating EGF signaling via LH receptor on GCs surrounding oocytes. Together, MVA pathway is a promising therapeutic target for prompting quality of oocytes from aged ovaries.
2023-02-26 | GSE175833 | GEO
Project description:The mechanisms of oocyte meiotic defects and low competence during ovarian aging remains elusive for decades. Using Hi-C (genome-wide chromatin conformation capture) and Smart RNA-seq of oocytes from 6- weeks or 10- months aged ovaries, the abnormal loose chromatin structures and disturbing expression of meiosis associated genes at metaphase I phase were disclosed. Furthermore, the transcriptomic landscape of granulosa cells (GCs) surrounding oocytes from young and aged ovaries reveled that oocyte meiotic maturation was accompanied with a robust increased expression of genes involved with the mevalonate (MVA) pathway in GCs from young ovaries but these genes expression was not upregulated to counterpart level in GCs from aged ovaries.The inhibitor of MVA pathway of GCs, Statins significantly decreased polar body extrusion rate and increased the rate of irregularly assembled spindles and misaligned chromosomes remarkably in oocytes of culumus-oocyte complex (COCs) from young ovaries . Correspondingly, the activitor of MVA pathway of GCs, Geranylgeraniol ameliorated ovarian reserve and reduced meiotic defects in oocytes of COCs from aged ovaries. Mechanistically, MVA pathway activation in GCs culminated oocyte meiotic maturation by upregulating EGF signaling via LH receptor on GCs surrounding oocytes. Together, MVA pathway is a promising therapeutic target for prompting quality of oocytes from aged ovaries.
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Project description:The mechanisms of oocyte meiotic defects and low competence during ovarian aging remains elusive for decades. Using Hi-C (genome-wide chromatin conformation capture) and Smart RNA-seq of oocytes from 6- weeks or 10- months aged ovaries, the abnormal loose chromatin structures and disturbing expression of meiosis associated genes at metaphase I phase were disclosed. Furthermore, the transcriptomic landscape of granulosa cells (GCs) surrounding oocytes from young and aged ovaries reveled that oocyte meiotic maturation was accompanied with a robust increased expression of genes involved with the mevalonate (MVA) pathway in GCs from young ovaries but these genes expression was not upregulated to counterpart level in GCs from aged ovaries.The inhibitor of MVA pathway of GCs, Statins significantly decreased polar body extrusion rate and increased the rate of irregularly assembled spindles and misaligned chromosomes remarkably in oocytes of culumus-oocyte complex (COCs) from young ovaries . Correspondingly, the activitor of MVA pathway of GCs, Geranylgeraniol ameliorated ovarian reserve and reduced meiotic defects in oocytes of COCs from aged ovaries. Mechanistically, MVA pathway activation in GCs culminated oocyte meiotic maturation by upregulating EGF signaling via LH receptor on GCs surrounding oocytes. Together, MVA pathway is a promising therapeutic target for prompting quality of oocytes from aged ovaries.
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Project description:The mechanisms of oocyte meiotic defects and low competence during ovarian aging remains elusive for decades. Using Hi-C (genome-wide chromatin conformation capture) and Smart RNA-seq of oocytes from 6- weeks or 10- months aged ovaries, the abnormal loose chromatin structures and disturbing expression of meiosis associated genes at metaphase I phase were disclosed. Furthermore, the transcriptomic landscape of granulosa cells (GCs) surrounding oocytes from young and aged ovaries reveled that oocyte meiotic maturation was accompanied with a robust increased expression of genes involved with the mevalonate (MVA) pathway in GCs from young ovaries but these genes expression was not upregulated to counterpart level in GCs from aged ovaries.The inhibitor of MVA pathway of GCs, Statins significantly decreased polar body extrusion rate and increased the rate of irregularly assembled spindles and misaligned chromosomes remarkably in oocytes of culumus-oocyte complex (COCs) from young ovaries . Correspondingly, the activitor of MVA pathway of GCs, Geranylgeraniol ameliorated ovarian reserve and reduced meiotic defects in oocytes of COCs from aged ovaries. Mechanistically, MVA pathway activation in GCs culminated oocyte meiotic maturation by upregulating EGF signaling via LH receptor on GCs surrounding oocytes. Together, MVA pathway is a promising therapeutic target for prompting quality of oocytes from aged ovaries.
2023-02-26 | GSE175830 | GEO
Project description:The mechanisms of oocyte meiotic defects and low competence during ovarian aging remains elusive for decades. Using Hi-C (genome-wide chromatin conformation capture) and Smart RNA-seq of oocytes from 6- weeks or 10- months aged ovaries, the abnormal loose chromatin structures and disturbing expression of meiosis associated genes at metaphase I phase were disclosed. Furthermore, the transcriptomic landscape of granulosa cells (GCs) surrounding oocytes from young and aged ovaries reveled that oocyte meiotic maturation was accompanied with a robust increased expression of genes involved with the mevalonate (MVA) pathway in GCs from young ovaries but these genes expression was not upregulated to counterpart level in GCs from aged ovaries.The inhibitor of MVA pathway of GCs, Statins significantly decreased polar body extrusion rate and increased the rate of irregularly assembled spindles and misaligned chromosomes remarkably in oocytes of culumus-oocyte complex (COCs) from young ovaries . Correspondingly, the activitor of MVA pathway of GCs, Geranylgeraniol ameliorated ovarian reserve and reduced meiotic defects in oocytes of COCs from aged ovaries. Mechanistically, MVA pathway activation in GCs culminated oocyte meiotic maturation by upregulating EGF signaling via LH receptor on GCs surrounding oocytes. Together, MVA pathway is a promising therapeutic target for prompting quality of oocytes from aged ovaries.
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Project description:Sustained Akt activation induces cardiac hypertrophy (LVH), which may lead to heart failure. This study tested the hypothesis that Akt activation contributes to mitochondrial dysfunction in pathological LVH. Akt activation induced LVH and progressive repression of mitochondrial fatty acid oxidation (FAO) pathways. Preventing LVH by inhibiting mTOR failed to prevent the decline in mitochondrial function but glucose utilization was maintained. Akt activation represses expression of mitochondrial regulatory, FAO, and oxidative phosphorylation genes in vivo that correlate with the duration of Akt activation in part by reducing FOXO-mediated transcriptional activation of mitochondrial-targeted nuclear genes in concert with reduced signaling via PPARα/PGC-1α and other transcriptional regulators. In cultured myocytes Akt activation disrupted mitochondrial bioenergetics, which could be partially reversed by maintaining nuclear FOXO, but not by increasing PGC-1α. Thus, although short-term Akt activation may be cardioprotective during ischemia by reducing mitochondrial metabolism and increasing glycolysis, long-term Akt activation in the adult heart contributes to pathological LVH in part by reducing mitochondrial oxidative capacity. Three samples per group of 8-week-old wild-type or transgenic mice with cardiac-specific constitutive expression of an activated Akt (caAkt) in the heart at 8 weeks of age were used. Mice have been previously described in depth (Shioi T, McMullen JR, Kang PM, Douglas PS, Obata T, Franke TF, Cantley LC, Izumo S. 2002. Akt/protein kinase B promotes organ growth in transgenic mice. Mol. Cell. Biol. 22:2799-2809.). After hearts were removed total myocardial RNA was labeled and processed as described below for microarray analysis to detail the global changes in gene expression underlying development of heart failure in this mouse model.
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Project description:Aberrant localization of proteins to mitochondria disturbs mitochondrial function and contributes to the pathogenesis of Huntington's disease (HD). However, the crucial factors and the molecular mechanisms remain elusive. Here, we found that heat shock transcription factor 1 (HSF1) accumulates in the mitochondria of HD cell models, a YAC128 mouse model, and human striatal organoids derived from HD induced pluripotent stem cells (iPSCs). Overexpression of mitochondria-targeting HSF1 (mtHSF1) in the striatum causes neurodegeneration and HD-like behavior in mice. Mechanistically, mtHSF1 facilitates mitochondrial fission by activating dynamin-related protein 1 (Drp1) phosphorylation at S616. Moreover, mtHSF1 suppresses single-stranded DNA-binding protein 1 (SSBP1) oligomer formation, which results in mitochondrial DNA (mtDNA) deletion. The suppression of HSF1 mitochondrial localization by DH1, a unique peptide inhibitor, abolishes HSF1-induced mitochondrial abnormalities and ameliorates deficits in an HD animal model and human striatal organoids. Altogether, our findings describe an unsuspected role of HSF1 in contributing to mitochondrial dysfunction, which may provide a promising therapeutic target for HD.
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