Defining the genetic basis of human respiratory chain disease
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PROVIDER: PRJNA75305 | ENA |
REPOSITORIES: ENA
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Project description:Defining the genetic basis of human respiratory chain disease
| PRJNA75307 | ENA
Project description:In response to cold, mammals activate brown fat for respiratory-dependent thermogenesis reliant on the electron transport chain. Yet, the structural basis of respiratory complex adaptation to cold remains elusive. Herein we combined thermoregulatory physiology and cryo-EM to study endogenous respiratory supercomplexes exposed to different temperatures. A cold-induced conformation of CI:III2 (termed type 2) was identified with a ~25 rotation of CIII2 around its inter-dimer axis, shortening inter-complex Q exchange space, and exhibiting different catalytic states which favor electron transfer. Large-scale supercomplex simulations in lipid membrane reveal how unique lipid-protein arrangements stabilize type 2 complexes to enhance catalytic activity. Together, our cryo-EM studies, multiscale simulations and biochemical analyses unveil the mechanisms and dynamics of respiratory adaptation at the structural and energetic level.
2024-10-02 | PXD054042 | Pride
Project description:To understand the common and opposite effects of mitochondrial and lysosomal perturbations on cellular signaling, we performed RNAseq in HeLa cells stably silenced for the mitochondrial respiratory chain subunit UQCRC1 (as a model of chronic mitochondrial respiratory chain deficiency), for lysosomal hydrolase acid alpla-glucosidase (GAA), or for lysosomal cathepsin B (CTSB). The controls were HeLa cells with scrambled shRNA.
2024-05-24 | GSE256471 | GEO
Project description:Primary mitochondrial respiratory chain (RC) diseases are heterogeneous in etiology and manifestations but collectively impair cellular energy metabolism. To identify a common cellular response to RC disease, systems biology level transcriptome investigations were performed in human RC disease skeletal muscle and fibroblasts. Global transcriptional and post-transcriptional dysregulation in a tissue-specific fashion was identified across diverse RC complex and genetic etiologies. RC disease muscle was characterized by decreased transcription of cytosolic ribosomal proteins to reduce energy-intensive anabolic processes, increased transcription of mitochondrial ribosomal proteins, shortened 5'-UTRs to improve translational efficiency, and stabilization of 3'-UTRs containing AU-rich elements. These same modifications in a reversed direction typified RC disease fibroblasts. RC disease also dysregulated transcriptional networks related to basic nutrient-sensing signaling pathways, which collectively mediate many aspects of tissue-specific cellular responses to primary RC disease. These findings support the utility of a systems biology approach to improve mechanistic understanding of mitochondrial RC disease. To identify a common cellular response to primary RC that might improve mechanistic understanding and lead to targeted therapies for human RC disease, we performed collective transcriptome profiling in skeletal muscle biopsy specimens and fibroblast cell lines (FCLs) of a diverse cohort of human mitochondrial disease subjects relative to controls. Systems biology investigations of common cellular responses to primary RC disease revealed a collective pattern of transcriptional, post-transcriptional and translational dysregulation occurring in a highly tissue-specific fashion. Affymetrix Human Exon 1.0ST microarray analysis was performed on 29 skeletal muscle samples and Fibroblast cell lines from mitochondrial disease patients and age- and gender-matched controls.
2013-07-01 | E-GEOD-42986 | biostudies-arrayexpress
Project description:Mitochondrial dysfunction induces a strong adaptive retrograde signaling response, however many of the down-stream effectors remain to be discovered. Here, we studied the shared transcriptional responses to three different mitochondrial respiratory chain inhibitors in human primary skin fibroblasts using QuantSeq 3’RNA-sequencing. We found that mevalonate pathway genes were concurrently downregulated irrespective of the respiratory chain complex affected. Targeted metabolomics demonstrated that impaired mitochondrial respiration at any of the three affected complexes also had functional consequences on the mevalonate pathway, reducing cholesterol precursor metabolites. A deeper study of complex I inhibition showed a reduced activity of ER-bound sterol sensing enzymes through impaired processing of the transcription factor SREBP2 and accelerated degradation of the ER cholesterol sensors SQLE and HMGCR. These adaptations of mevalonate pathway activity neither affected total intracellular cholesterol levels nor the cellular free (non-esterified) cholesterol pool. Measurement of intracellular cholesterol using the fluorescent cholesterol binding dye filipin revealed that complex I inhibition elevated cholesterol on intracellular compartments. Our study shows that mitochondrial respiratory chain dysfunction elevates intracellular free cholesterol levels and therefore attenuates the expression of mevalonate pathway enzymes, which lowers endogenous cholesterol biosynthesis, disrupting the metabolic output of the mevalonate pathway. Intracellular disturbances in cholesterol homeostasis may alter systemic cholesterol management in diseases associated with declining mitochondrial function.
2022-02-25 | GSE191034 | GEO
Project description:Primary mitochondrial respiratory chain (RC) diseases are heterogeneous in etiology and manifestations but collectively impair cellular energy metabolism. To identify a common cellular response to RC disease, systems biology level transcriptome investigations were performed in human RC disease skeletal muscle and fibroblasts. Global transcriptional and post-transcriptional dysregulation in a tissue-specific fashion was identified across diverse RC complex and genetic etiologies. RC disease muscle was characterized by decreased transcription of cytosolic ribosomal proteins to reduce energy-intensive anabolic processes, increased transcription of mitochondrial ribosomal proteins, shortened 5'-UTRs to improve translational efficiency, and stabilization of 3'-UTRs containing AU-rich elements. These same modifications in a reversed direction typified RC disease fibroblasts. RC disease also dysregulated transcriptional networks related to basic nutrient-sensing signaling pathways, which collectively mediate many aspects of tissue-specific cellular responses to primary RC disease. These findings support the utility of a systems biology approach to improve mechanistic understanding of mitochondrial RC disease. To identify a common cellular response to primary RC that might improve mechanistic understanding and lead to targeted therapies for human RC disease, we performed collective transcriptome profiling in skeletal muscle biopsy specimens and fibroblast cell lines (FCLs) of a diverse cohort of human mitochondrial disease subjects relative to controls. Systems biology investigations of common cellular responses to primary RC disease revealed a collective pattern of transcriptional, post-transcriptional and translational dysregulation occurring in a highly tissue-specific fashion.
2013-07-01 | GSE42986 | GEO
Project description:Cryo-EM Structure of the bcc-aa3 respiratory chain supercomplex from Corynebacterium glutamicum
2019-05-29 | MSV000083873 | MassIVE
Project description:Accumulation of mitochondrial DNA (mtDNA) deletions to detrimental levels in few cells and chronic inflammation are concomitant during aging in many tissues, thus raising the question of a causal link between both phenomena. To approach this, we generated mice which accumulate such deletions in the epidermis by expression of a mutant TWINKLE helicase in keratinocytes. These short-lived mice showed a severe depletion of mtDNA, as well as low amounts of large-scale deletions in the epidermis. These alterations led to an imbalanced stoichiometry of mitochondrial respiratory chain complexes, inducing a unique combination of cytokine expression in the epidermis. This caused a severe inflammatory phenotype, with massive immune cell infiltrates already before birth, resulting in serous scabs at the ventral skin region and limb joints. Altogether, these data suggest that severe respiratory chain dysfunction, as observed in a few cells in aged tissues, might be involved in the development of chronic inflammation.
2017-08-16 | GSE97242 | GEO
Project description:The mammalian respiratory chain complexes I, III2 and IV (CI, CIII2 and CIV) are critical for cellular bioenergetics and form a stable assembly, the respirasome (CI-CIII2-CIV), that is biochemically and structurally well documented. The role of the respirasome in bioenergetics and regulation of metabolism is subject to intense debate and is difficult to study because the individual respiratory chain complexes coexist together with high levels of respirasomes. To critically investigate the in vivo role of the respirasome, we generated homozygous knock-in mice that have normal levels of respiratory chain complexes but profoundly decreased levels of respirasomes. Surprisingly, the mutant mice are healthy, with preserved respiratory chain capacity and normal exercise performance. Our findings show that high levels of respirasomes are dispensable for maintaining bioenergetics and physiology in the mouse, but raises questions about their alternate functions, such as relating to regulation of protein stability and prevention of age-associated protein aggregation.
2024-03-19 | PXD023846 | Pride
Project description:A fuller study of UV-induced biological effects lies beyond the scope of this paper. I will focus on the genetic interaction of cells irradiated by UV. Accordingly, in respect to genomic, the regulation of the gene expressions in cells represents how they response to the stress and repair themselves. In the past, Northern Blot has been used to detect the expression level of a few genes in one experiment. Thus, this assay is always limited to a small scope of a huge unknown network of gene expression. However, to investigate gene expression networks made of thousands of genes, a powerful tool must be implemented. As anticipated, the interactions between regulated genes in UV irradiation time-course experiment can be analyzed by cDNA microarray analysis with experimental loop design. This study provides a platform to investigate the gene networks regulated by UV irradiation. Keywords: UV, cDNA microarray, mitochondria respiratory chain, ROS, carcinogenesis
2006-11-17 | GSE3623 | GEO