Mitochondrial mistranslation is modulated by metabolic stress
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ABSTRACT:
PROVIDER: PRJNA667352 | ENA |
REPOSITORIES: ENA
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Project description:Changes in the rate and fidelity of mitochondrial protein synthesis impact the metabolic and physiological roles of mitochondria. Here we explored how environmental stress in the form of a high-fat diet modulates mitochondrial translation using mutant mice with error-prone (Mrps12ep/ep) or hyper-accurate (Mrps12ha/ha) mitochondrial ribosomes. Intriguingly, although both mutations are metabolically beneficial in reducing body weight, decreasing circulating insulin and increasing glucose tolerance during a high-fat diet, they manifest divergent (either deleterious or beneficial) outcomes in a tissue-specific manner. In two distinct organ types that are commonly affected by metabolic disease, the heart and the liver, Mrps12ep/ep mice were protected against heart defects but sensitive towards lipid accumulation in the liver, activating genes involved in steroid and amino acid metabolism. In contrast, enhanced translational accuracy in Mrps12ha/ha mice protected the liver from a high-fat diet through activation of liver proliferation programs, but enhanced the development of severe hypertrophic cardiomyopathy. While these findings reflect the complex transcriptional and cell signalling responses that differ between post-mitotic (heart) and highly proliferative (liver) tissues, they also suggest that trade-offs between the rate and fidelity of mitochondrial protein synthesis dictate tissue-specific outcomes toward commonly encountered stressful environmental conditions.
2021-06-22 | GSE159014 | GEO
Project description:Changes in the rate and fidelity of mitochondrial protein synthesis impact the metabolic and physiological roles of mitochondria. Here we explored how environmental stress in the form of a high fat diet modulates mitochondrial translation using mutant mice with error-prone (Mrps12ep/ep) or hyper-accurate (Mrps12ha/ha) mitochondrial ribosomes. We find that while, metabolically both mutations are beneficial in reducing body weight, decreasing circulating insulin and increasing glucose tolerance they cause tissue specific defects when placed on a high fat diet. In contrast to the effect of the mutations on a normal diet the Mrps12ha/ha mice show more pronounced phenotypic and molecular defects as a result of the slow, accurate nature of their protein synthesis. While the Mrps12ep/ep mice accumulate more fat, exhibit larger vacuoles in the liver and lose glucose tolerance, the Mrps12ha/ha mice develop severe hypertrophic cardiomyopathy and hypoxia due to the stress of the diet, showing that benefit or detriment of error-prone and hyper-accurate protein synthesis in mitochondria is dependent on tissue and environmental conditions.
2021-09-09 | PXD021762 | Pride
Project description:Changes in the rate and fidelity of mitochondrial protein synthesis impact the metabolic and physiological roles of mitochondria. Here we explored how environmental stress in the form of a high-fat diet modulates mitochondrial translation using mutant mice with error-prone (Mrps12ep/ep) or hyper-accurate (Mrps12ha/ha) mitochondrial ribosomes and their effects on lifespan. Intriguingly, although both mutations are metabolically beneficial in reducing body weight, decreasing circulating insulin and increasing glucose tolerance during a high-fat diet, they manifest divergent (either deleterious or beneficial) outcomes in a tissue-specific manner. In two distinct organ types that are commonly affected by metabolic disease, the heart and the liver, Mrps12ep/ep mice were protected against heart defects but sensitive towards lipid accumulation in the liver, activating genes involved in steroid and amino acid metabolism. In contrast, enhanced translational accuracy in Mrps12ha/ha mice protected the liver from a high-fat diet through activation of liver proliferation programs, but enhanced the development of severe hypertrophic cardiomyopathy and led to reduced lifespan. While these findings reflect the complex transcriptional and cell signalling responses that differ between post-mitotic (heart) and highly proliferative (liver) tissues, they also suggest that trade-offs between the rate and fidelity of mitochondrial protein synthesis dictate tissue-specific outcomes toward commonly encountered stressful environmental conditions or aging.
2021-09-10 | PXD024633 | Pride
Project description:The fidelity of translation is crucial in prokaryotes and for the nuclear-encoded proteins of eukaryotes, however little is known about the role of mistranslation in mitochondria and its effects on metabolism. We generated yeast and mouse models with error-prone and hyperaccurate mitochondrial translation fidelity and found that translation rate is more important than translational accuracy for cell function in mammals. We found that mitochondrial mistranslation reduces overall mitochondrial translation and the rate of respiratory complex assembly, however in mammals this is compensated for by increased mitochondrial protein stability and upregulation of the citric acid cycle. Moreover, mitochondrial stress signaling enables the recovery of mitochondrial translation via mitochondrial biogenesis, telomerase expression and cell proliferation, normalizing metabolism. Conversely, we show that increased fidelity of mitochondrial translation reduces the rate of protein synthesis without eliciting the mitochondrial stress response. Consequently, the rate of translation cannot be recovered causing dilated cardiomyopathy. Our findings reveal mammalian specific signaling pathways that can respond to changes in the fidelity of mitochondrial protein synthesis
2019-11-08 | PXD015456 | Pride
Project description: Not available
| S-EPMC8282274 | biostudies-literature
Project description:Fibroblast growth factor 21 (FGF21) is a key metabolic regulator which was recently discovered as stress-induced myokine and common denominator of muscle mitochondrial disease. However, its precise function and pathophysiological relevance remains unknown. Here we demonstrate that white adipose tissue (WAT) is the major target of muscle mitochondrial stress-induced FGF21. Strikingly, substantial browning and metabolic remodeling of subcutaneous WAT, together with the reduction of circulating triglycerides and cholesterol are fully FGF21 dependent. Unexpectedly and in contrast to prior expectations, we found a negligible role of FGF21 in muscle stress-related improved glycemic control, obesity resistance and hepatic lipid homeostasis. Furthermore, we show that the protective muscle mitohormesis and metabolic stress adaptation does not require FGF21 action. Taken together, our data imply that although FGF21 drives WAT remodeling, this effect and FGF21 as stress hormone per se may not be essential for the adaptive response under muscle mitochondrial stress conditions. Wildtype male mice and FGF21-knockout male mice, together with muscle specific UCP1-transgenic male animals, and double cross of FGF21-KO with UCP1-Tg male mice, were kept on a standardized low fat diet for 40 weeks. After sacrifice, subcutaneous white adipose tisseu (scWAT) was rapidly removed, weighed, and snap frozen in liquid nitrogen and used for RNA isolation and whole genome gene expression microarray hybridisation using Agilent arrays.
2016-01-07 | E-GEOD-71749 | biostudies-arrayexpress
Project description:Fibroblast growth factor 21 (FGF21) is a key metabolic regulator which was recently discovered as stress-induced myokine and common denominator of muscle mitochondrial disease. However, its precise function and pathophysiological relevance remains unknown. Here we demonstrate that white adipose tissue (WAT) is the major target of muscle mitochondrial stress-induced FGF21. Strikingly, substantial browning and metabolic remodeling of subcutaneous WAT, together with the reduction of circulating triglycerides and cholesterol are fully FGF21 dependent. Unexpectedly and in contrast to prior expectations, we found a negligible role of FGF21 in muscle stress-related improved glycemic control, obesity resistance and hepatic lipid homeostasis. Furthermore, we show that the protective muscle mitohormesis and metabolic stress adaptation does not require FGF21 action. Taken together, our data imply that although FGF21 drives WAT remodeling, this effect and FGF21 as stress hormone per se may not be essential for the adaptive response under muscle mitochondrial stress conditions.
2016-01-07 | GSE71749 | GEO
Project description:Metabolic dysfunction associated steatotic liver disease (MASLD) is characterized by a constant accumulation of lipids in the liver. This lipotoxicity in the liver is associated with dysregulation of the first step in lipid catabolism called beta oxidation in the mitochondrial matrix, eventually leading to mitochondrial dysfunction. To evaluate possible involvement of mitochondrial DNA methylation in this lipid metabolic dysfunction we investigated the functional metabolic effects of mitochondrial overexpression of CpG (MSssI) and GpC (MCviPI) DNA methyltransferases in relation to gene expression and (mito)epigenetic signatures. Overall, the results show that mitochondrial GpC and to a lesser extent CpG methylation increase bile acid metabolic gene expression, inducing cholestasis by mito-nuclear epigenetic reprogramming. Moreover, increased expression of metabolic nuclear receptors in both MSssI and MCviPI cells promote mitochondrial swelling and induce basal overactivation of mitochondrial respiration which favours lipid accumulation and metabolic-stress induced mitophagy and autophagy stress responses. Altogether GpC and CpG mitochondrial induce a metabolic challenging environment that is similar to mitochondrial dysfunction in the progression of MASLD.
2023-12-08 | GSE240988 | GEO
Project description:Metabolic dysfunction associated steatotic liver disease (MASLD) is characterized by a constant accumulation of lipids in the liver. This lipotoxicity in the liver is associated with dysregulation of the first step in lipid catabolism called beta oxidation in the mitochondrial matrix, eventually leading to mitochondrial dysfunction. To evaluate possible involvement of mitochondrial DNA methylation in this lipid metabolic dysfunction we investigated the functional metabolic effects of mitochondrial overexpression of CpG (MSssI) and GpC (MCviPI) DNA methyltransferases in relation to gene expression and (mito)epigenetic signatures. Overall, the results show that mitochondrial GpC and to a lesser extent CpG methylation increase bile acid metabolic gene expression, inducing cholestasis by mito-nuclear epigenetic reprogramming. Moreover, increased expression of metabolic nuclear receptors in both MSssI and MCviPI cells promote mitochondrial swelling and induce basal overactivation of mitochondrial respiration which favours lipid accumulation and metabolic-stress induced mitophagy and autophagy stress responses. Altogether GpC and CpG mitochondrial induce a metabolic challenging environment that is similar to mitochondrial dysfunction in the progression of MASLD.
2023-12-08 | GSE241526 | GEO
Project description:To investigate how organisms mitigate the deleterious effects of mistranslation during evolution, a mutant tRNA was expressed in S. cerevisiae. The expression of Candida Ser-tRNACAG from a low copy plasmid in S. cerevisiae promoted mistranslation events by random incorporation of both serine and leucine at CUG codons. As mistranslation causes an overload of the protein quality pathways, it disrupts cellular protein homeostasis leading to a major fall in fitness. Laboratory evolutionary experiments were performed to study whether the fitness cost of mistranslation can be lowered. We also wanted to identify the cost-reduction strategy: reducing the frequencies of errors (mitigation), or increasing tolerance to errors (robustness), either by global or local activities.
2015-11-06 | GSE65718 | GEO