Age-associated decline of MondoA drives cellular senescence through impaired autophagy and mitochondrial homeostasis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA741923 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14929929_1.fastq.gz | Fastqsanger.gz | |||
| SRR14929929_2.fastq.gz | Fastqsanger.gz | |||
| SRR14929930_1.fastq.gz | Fastqsanger.gz | |||
| SRR14929930_2.fastq.gz | Fastqsanger.gz | |||
| SRR14929931_1.fastq.gz | Fastqsanger.gz |
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Project description:Accumulation of senescent cells affects organismal aging and the prevalence of age-associated disease. Emerging evidence suggests that activation of autophagy protects against age-associated diseases and promotes longevity, but the roles and regulatory mechanisms of autophagy in cellular senescence are not well understood. Here we identified the transcription factor, MondoA, as a novel regulator of cellular senescence, autophagy and mitochondrial homeostasis. MondoA protected against cellular senescence by activating autophagy partly through the suppression of an autophagy negative regulator, Rubicon. In addition, we identified peroxiredoxin 3 (Prdx3) as another downstream regulator of MondoA essential for mitochondrial homeostasis and autophagy. Rubicon and Prdx3 worked independently to regulate senescence. Furthermore, we found that MondoA knockout mice had exacerbated senescence during ischemic acute kidney injury (AKI), and a decrease of MondoA in the nucleus was correlated with human aging and ischemic AKI. Our results suggest that retaining MondoA activity protects from senescence and age-associated disease.
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Project description:The decline of endothelial autophagy is closely related to vascular senescence and disease, although the molecular mechanisms connecting these outcomes in vascular endothelial cells (VECs) remain unclear. Here, we identify a crucial role for CD44, a multifunctional adhesion molecule, in controlling autophagy and aging in VECs. The CD44 intercellular domain (CD44ICD) negatively regulates autophagy by reducing PIK3R4 and PIK3C3 levels and disrupting STAT3-dependent PtdIns3K complexes. CD44 and its homologue clec-31 are increased in aging vascular endothelium and Caenorhabditis elegans, respectively, suggesting that an age-dependent increase in CD44 induces autophagy decline and aging phenotypes. Accordingly, CD44 knockdown ameliorates age-associated phenotypes in VECs. The endothelium-specific CD44ICD knock-in mouse is shorter-lived, with VECs exhibiting obvious premature aging characteristics associated with decreased basal autophagy. Autophagy activation suppresses the premature aging of human and mouse VECs overexpressing CD44ICD, function conserved in the CD44 homologue clec-31 in C. elegans. Our work describes a mechanism coordinated by CD44 function bridging autophagy decline and aging.
2023-08-30 | GSE236523 | GEO
Project description:The glucose-sensing Mondo pathway regulates expression of metabolic genes in mammals. Here, we have revealed an unexpected role of this pathway in vertebrate embryonic development. We characterized Mondo pathway function in the zebrafish and showed that knock-down of mondoa impaired the early morphogenetic movement of epiboly in zebrafish embryos. Expression of nsdhl , an enzyme of cholesterol and pregnenolone synthesis, was strongly reduced in these embryos. Loss of Nsdhl function likewise impaired epiboly and led to microtubule cytoskeleton defects in the embryo, similar to MondoA loss of function. Both epiboly and microtubule cytoskeleton defects were partially restored by pregnenolone treatment. Gene disruption of mondoa perturbed epiboly with only partial penetrance, likely due to compensatory changes in the expression of cholesterol/steroid metabolism genes. Collectively, our results show a novel role for MondoA in the regulation of early vertebrate development, connecting glucose, cholesterol and steroid hormone metabolism with early embryonic cell movements.
2020-09-11 | GSE144349 | GEO
Project description:The glucose-sensing Mondo pathway regulates expression of metabolic genes in mammals. Here, we have revealed an unexpected role of this pathway in vertebrate embryonic development. We characterized Mondo pathway function in the zebrafish and showed that knock-down of mondoa impaired the early morphogenetic movement of epiboly in zebrafish embryos. Expression of nsdhl , an enzyme of cholesterol and pregnenolone synthesis, was strongly reduced in these embryos. Loss of Nsdhl function likewise impaired epiboly and led to microtubule cytoskeleton defects in the embryo, similar to MondoA loss of function. Both epiboly and microtubule cytoskeleton defects were partially restored by pregnenolone treatment. Gene disruption of mondoa perturbed epiboly with only partial penetrance, likely due to compensatory changes in the expression of cholesterol/steroid metabolism genes. Collectively, our results show a novel role for MondoA in the regulation of early vertebrate development, connecting glucose, cholesterol and steroid hormone metabolism with early embryonic cell movements.
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Project description:We test the idea that peripheral cellular senescence is a major driver of age-related cognitive impairment, such that treatment with the brain impermeable senolytic, ABT-263, can preserve cognition and markers of brain aging thought to underlie cognitive decline. Male F344 rats were treated from 12-18 months of age with quercetin + dasatinib or ABT-263 or vehicle and were compared to young (6 month). Senolytic treatments had similar effects in decreasing peripheral markers of senescence and the senescence-associated secretory phenotype (SASP), including plasma levels of several cytokines, rescued memory and hippocampal synaptic transmission, and decreased expression of immune response genes in the dentate gyrus (DG). Across senolytic treatment groups, differential DG gene expression was observed for cellular senescence and pathways linked to senescence, including negative regulation of cell death, ribosomes, and microglial activation consistent with differential access of dasatinib and ABT-263 to the brain. Finally, both senolytic treatments preserved the blood-brain barrier suggesting that leakage of clinically significant amounts of ABT-263 into the brain is unlikely. The results indicate that preserved cognition was due to removal of peripheral senescent cells, decreasing systemic inflammation that normally drives neuroinflammation, BBB breakdown, and impaired synaptic function.
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Project description:Somatic mitochondrial DNA (mtDNA) mutations contribute to the pathogenesis of age-related disorders, including myelodysplastic syndromes (MDS). The accumulation of mitochondria harboring mtDNA mutations in patients with these disorders suggests a failure of normal mitochondrial quality-control systems. The mtDNA-mutator mice acquire somatic mtDNA mutations via a targeted defect in the proofreading function of the mtDNA polymerase, PolgA, and develop macrocyticanemia similar to that of patients with MDS. We observed an unexpected defect in clearance of dysfunctional mitochondria at specific stages during erythroid maturation in hematopoietic cells from aged mtDNA-mutator mice. Mechanistically, aberrant activation of mechanistic target of rapamycin signaling and phosphorylation of uncoordinated 51-like kinase (ULK) 1 in mtDNA-mutator mice resulted in proteasome mediated degradation of ULK1 and inhibition of autophagy in erythroid cells. To directly evaluate the consequence of inhibiting autophagy on mitochondrial function in erythroid cells harboring mtDNA mutations in vivo, we deleted Atg7 from erythroid progenitors of wildtype and mtDNA-mutator mice. Genetic disruption of autophagy did not cause anemia in wild-type mice but accelerated the decline in mitochondrial respiration and development of macrocytic anemia in mtDNA-mutator mice. These findings highlight a pathological feedback loop that explains how dysfunctional mitochondria can escape autophagy-mediated degradation and propagate in cells predisposed to somatic mtDNA mutations, leading to disease. We used microarrays to identify expression profiles and pathways that are differentially activated or suppressed in Ter119+ bone marrow cells isolated from phlebotomized wildtype or Polg mutant mice
2015-04-21 | E-GEOD-57761 | biostudies-arrayexpress
Project description:Human MondoA requires glucose as well as other modulatory signals to function in transcription. One such signal is acidosis, which increases MondoA activity and also drives a protective gene signature breast cancer. How low pH controls MondoA transcriptional activity is unknown. We found that low pH medium increases mitochondrial ATP (mtATP), which is subsequently exported from the mitochondrial matrix. Mitochondria-bound hexokinase transfers a phosphate from mtATP to cytoplasmic glucose to generate glucose-6-phosphate (G6P), which is an established MondoA activator. The outer mitochondrial membrane localization of MondoA suggests that it is positioned to coordinate the adaptive transcriptional response to a cell’s most abundant energy sources, cytoplasmic glucose and mtATP. In response to acidosis, MondoA shows preferential binding to just two targets, TXNIP and its paralog ARRDC4. Because these transcriptional targets are suppressors of glucose uptake we propose that MondoA is critical for restoring metabolic homeostasis in response to high energy charge.
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Project description:CD44 connects autophagy decline and aging in the vascular endothelium
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Project description:In order to investigate the effect of MondoA loss on the expression of Myc-dependent genes, we performed a microarray analysis from RNAs isolated from TET21N cells expressing either control (siControl) or MondoA (siMondoA) siRNAs either with (NT) or without (Doxy) induced N-Myc expression. TET21N cells were grown in medium with either Doxy (Myc-Off) or No Treatment (Myc-On), then transiently transfected with either non-specific siRNA or MondoA siRNA in replicates. Cells were then lysed and RNA isolated.
2015-01-01 | E-GEOD-55538 | biostudies-arrayexpress