Effects of different diets on autophagy control and unfolded protein response in the aging heart
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE299132 | GEO | 2026/01/28
REPOSITORIES: GEO
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Project description:Effects of different diets on autophagy control and unfolded protein response in the aging heart
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Project description:RNA ligation can regulate RNA function by altering RNA sequence, structure and coding potential. For example, the function of XBP1 in mediating the unfolded protein response requires RNA ligation, as does the maturation of some tRNAs. Here, we describe a novel in vivo model in C. elegans for the conserved RNA ligase RtcB, and show that RtcB ligates the xbp 1 mRNA during the IRE 1 branch of the unfolded protein response. Without RtcB, protein stress results in the accumulation of unligated xbp-1 mRNA fragments, defects in the unfolded protein response, and decreased lifespan. RtcB also ligates endogenous pre tRNA halves, and RtcB mutants have defects in growth and lifespan that can be bypassed by expression of pre-spliced tRNAs. In addition, animals that lack RtcB have defects that are independent of tRNA maturation and the unfolded protein response. Thus, RNA ligation by RtcB is required for the function of multiple endogenous target RNAs including both xbp-1 and tRNAs. RtcB is uniquely capable of performing these ligation functions, and RNA ligation by RtcB mediates multiple essential processes in vivo.
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Project description:Metabolic diseases are strongly associated with endoplasmic reticulum (ER) stress. Upon ER stress, the unfolded protein response (UPR) is activated to limit cellular damage. However, escalating cellular UPR response weakens with age. Here, we show that 5-day-old Caenorhabditis elegans fed a bacteria diet with 2% glucose (high glucose diet, HGD-5) extend their lifespan while shortening the lifespan of 1-day-old (HGD-1) animals. We observed a metabolic shift in HGD-1 as glucose and fertility synergistically prolonged the lifespan of HGD-5, independently of DAF-16. Notably, we identified that UPR stress sensors ATF-6 and PEK-1 extended the longevity of HGD-5 worms, while the ire-1 ablation drastically increased HGD-1 lifespan. Based on these observations, we postulate that HGD activates the otherwise quiescent UPR in aged worms to overcome ageing-related stress and restore ER homeostasis. In contrast, young animals subjected to HGD provokes unresolved ER stress, conversely leading to a detrimental stress response.
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Project description:Mitochondrial stress during development causes widespread changes in chromatin structure to promote mitochondrial unfolded protein response (UPRmt), perpetuating an early response across a lifetime results in lifespan extension. We found that the nucleosome remodeling and deacetylase (NuRD) complex interact with the transcription factor DVE-1 to initiate the global chromatin condensation and induce the UPRmt in animals experienced with mild mitochondrial dysfunction. The condensed chromatin structure can be well maintained into later life that is beneficial for lifespan extension. Moreover, overexpression of the core component of the NuRD complex is sufficient to induce the UPRmt response and longevity in C. elegans. Thus, a transient mitochondrial stress response during early development is established and propagated into later life through the NuRD-dependent chromatin remodeling pathway to extend lifespan.
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Project description:Inadequate extracellular conditions can adversely affect the environment of the ER and impinge on the maturation of nascent proteins. The resultant accumulation of unfolded proteins activates a signal transduction pathway, known as the unfolded protein response, which serves primarily to protect the cell during stress and helps restore homeostasis to the ER. Microarray analysis of the unfolded protein response in a human medulloblastoma cell line treated with thapsigargin revealed that, in addition to known targets, a large number of proangiogenic factors were up-regulated. Real-time PCR analyses confirmed that four of these factors, VEGF, FGF2, angiogenin and IL-8, were transcriptionally up-regulated in multiple cell lines by various ER stress inducers. Our studies on VEGF regulation revealed that XBP-1(S), a UPR-inducible transcription factor, bound to two regions on the VEGF promoter, and analysis of XBP-1 null mouse embryonic fibroblasts revealed that it contributes to VEGF expression in response to ER stress. ATF4, another UPR-inducible transcription factor, also binds to the VEGF gene, although its contribution to VEGF transcription appeared to be fairly modest. We also found that VEGF mRNA stability is increased in response to UPR activation, via activation of the AMP and p38MAP kinases, demonstrating that increased mRNA levels occur at two regulatory points. In keeping with the mRNA levels, we found that VEGF protein is secreted at levels as high as or higher than that achieved in response to hypoxia. Our results indicate that the UPR plays a significant role in inducing positive regulators of angiogenesis. It also regulates VEGF expression at multiple levels and is likely to have widespread implications for promoting angiogenesis in response to normal physiological cues as well as in pathological conditions like cancer. We used microarrays to perform genome wide expression analysis in Daoy medulloblastoma cells to identify gene profiles that change in response to thapsigargin treatment which causes induction of the unfolded protein response.
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