Kidney-specific selection of mitochondrial TrnE mutation leads to mitochondrial kidney disease [scRNA-Seq]
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ABSTRACT:
PROVIDER: PRJNA1133774 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR29758381_1.fastq.gz | Fastqsanger.gz | |||
| SRR29758381_2.fastq.gz | Fastqsanger.gz | |||
| SRR29758382_1.fastq.gz | Fastqsanger.gz | |||
| SRR29758382_2.fastq.gz | Fastqsanger.gz | |||
| SRR29758383_1.fastq.gz | Fastqsanger.gz |
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Project description:Kidney-specific selection of mitochondrial TrnE mutation leads to mitochondrial kidney disease
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Project description:Kidney-specific selection of mitochondrial TrnE mutation leads to mitochondrial kidney disease [RNA-Seq]
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Project description:Heteroplasmic pathogenic mitochondrial DNA (mtDNA) mutations are known to cause mitochondrial diseases with varied clinical symptoms. The tissue-specific selection of heteroplasmic pathogenic mtDNA mutations and its correlation with clinical and pathological outcomes remains to be elucidated. To date, negative selection of pathogenic mutations has been observed in a limited range of cell types, including female germ cells, blood cells, particularly T cells, and intestinal epithelial cells. However, evidence of positive selection in any tissue or cell type has not been reported. In this study, we utilized the DddA-derived cytosine base editor (DdCBE) technique to generate a heteroplasmic pathogenic mutant mouse model harboring a mutation in the mito-tRNA Glu anticodon arm site. Over a two-year longitudinal investigation, we assessed the mutational selection dynamics in eight solid organs and blood from this model. Our findings reveal a significant positive selection for pathogenic mtDNA in the kidney and liver. Notably, the kidney exhibited mitochondrial kidney disease during aging, reflecting the clinical kidney defects observed in patients with mito-tRNA mutations. Intriguingly, disparate selection patterns emerged within multiple cell types of kidneys, with tubular epithelial cells and podocytes presenting positive selection, whereas immune cells exhibited purifying selection. Leveraging Sc-RNA seq and Stereo-seq, we identified Clu and Spp1 as molecular markers of the high mutant kidney tubular epithelial cells and suggest that up-regulation of these markers may activate the p-AKT pathway, thereby increasing the proliferation of high mutant tubular epithelial cells, hence leads to the positive selection on this site in mutant kidneys during aging. Our comprehensive analysis provides compelling evidence for the significance of tissue-specific selection of pathogenic mtDNA mutations. This study enhances our understanding of the mechanistic links between tissue-specific selection and mitochondrial disease pathogenesis, paving the way for the development of targeted therapeutic strategies in the future.
2025-06-16 | GSE282115 | GEO
Project description:Heteroplasmic pathogenic mitochondrial DNA (mtDNA) mutations are known to cause mitochondrial diseases with varied clinical symptoms. The tissue-specific selection of heteroplasmic pathogenic mtDNA mutations and its correlation with clinical and pathological outcomes remains to be elucidated. To date, negative selection of pathogenic mutations has been observed in a limited range of cell types, including female germ cells, blood cells, particularly T cells, and intestinal epithelial cells. However, evidence of positive selection in any tissue or cell type has not been reported. In this study, we utilized the DddA-derived cytosine base editor (DdCBE) technique to generate a heteroplasmic pathogenic mutant mouse model harboring a mutation in the mito-tRNA Glu anticodon arm site. Over a two-year longitudinal investigation, we assessed the mutational selection dynamics in eight solid organs and blood from this model. Our findings reveal a significant positive selection for pathogenic mtDNA in the kidney and liver. Notably, the kidney exhibited mitochondrial kidney disease during aging, reflecting the clinical kidney defects observed in patients with mito-tRNA mutations. Intriguingly, disparate selection patterns emerged within multiple cell types of kidneys, with tubular epithelial cells and podocytes presenting positive selection, whereas immune cells exhibited purifying selection. Leveraging Sc-RNA seq and Stereo-seq, we identified Clu and Spp1 as molecular markers of the high mutant kidney tubular epithelial cells and suggest that up-regulation of these markers may activate the p-AKT pathway, thereby increasing the proliferation of high mutant tubular epithelial cells, hence leads to the positive selection on this site in mutant kidneys during aging. Our comprehensive analysis provides compelling evidence for the significance of tissue-specific selection of pathogenic mtDNA mutations. This study enhances our understanding of the mechanistic links between tissue-specific selection and mitochondrial disease pathogenesis, paving the way for the development of targeted therapeutic strategies in the future.
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Project description:Heteroplasmic pathogenic mitochondrial DNA (mtDNA) mutations are known to cause mitochondrial diseases with varied clinical symptoms. The tissue-specific selection of heteroplasmic pathogenic mtDNA mutations and its correlation with clinical and pathological outcomes remains to be elucidated. To date, negative selection of pathogenic mutations has been observed in a limited range of cell types, including female germ cells, blood cells, particularly T cells, and intestinal epithelial cells. However, evidence of positive selection in any tissue or cell type has not been reported. In this study, we utilized the DddA-derived cytosine base editor (DdCBE) technique to generate a heteroplasmic pathogenic mutant mouse model harboring a mutation in the mito-tRNA Glu anticodon arm site. Over a two-year longitudinal investigation, we assessed the mutational selection dynamics in eight solid organs and blood from this model. Our findings reveal a significant positive selection for pathogenic mtDNA in the kidney and liver. Notably, the kidney exhibited mitochondrial kidney disease during aging, reflecting the clinical kidney defects observed in patients with mito-tRNA mutations. Intriguingly, disparate selection patterns emerged within multiple cell types of kidneys, with tubular epithelial cells and podocytes presenting positive selection, whereas immune cells exhibited purifying selection. Leveraging Sc-RNA seq and Stereo-seq, we identified Clu and Spp1 as molecular markers of the high mutant kidney tubular epithelial cells and suggest that up-regulation of these markers may activate the p-AKT pathway, thereby increasing the proliferation of high mutant tubular epithelial cells, hence leads to the positive selection on this site in mutant kidneys during aging. Our comprehensive analysis provides compelling evidence for the significance of tissue-specific selection of pathogenic mtDNA mutations. This study enhances our understanding of the mechanistic links between tissue-specific selection and mitochondrial disease pathogenesis, paving the way for the development of targeted therapeutic strategies in the future.
2025-06-16 | GSE282114 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2025-06-16 | GSE282116 | GEO
Project description:Kidney is a vital organ responsible for homeostasis in the body. To retard kidney aging is of great importance for maintaining body health. Whereas the therapeutic strategies targeting against kidney aging are not elucidated. Recent studies show mitochondrial dysfunction is critical for renal tubular cell senescence and kidney aging, however, the underlying mechanisms of mitochondrial dysfunction in kidney aging have not been demonstrated. Herein, we found calcium overload, and the mitochondrial calcium uniporter (MCU) was induced in renal tubular cells and aged kidney. To activate MCU not only triggered mitochondrial calcium overload, but also induced reactive oxygen species (ROS) production and cellular senescence and age-related kidney fibrosis. Inversely, to block MCU or chelate calcium diminished ROS generation, restored mitochondrial homeostasis, and retarded cell senescence and protected against kidney aging. These results demonstrate MCU plays a key role in promote renal tubular cell senescence, which provides a new insight on the therapeutic strategy for fighting against kidney aging.
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Project description:This set of arrays contains all microarray experiments done involving comparisons among C. elegans natural isolates and mutation-accumulation lines. Abstract: The evolutionary importance of gene-expression divergence is unclear: some studies suggest that it is an important mechanism for evolution by natural selection, whereas others claim that most between-species regulatory changes are neutral or nearly neutral. We examined global transcriptional divergence patterns in a set of Caenorhabditis elegans mutation-accumulation lines and natural isolate lines to provide insights into the evolutionary importance of transcriptional variation and to discriminate between the forces of mutation and natural selection in shaping the evolution of gene expression. We detected the effects of selection on transcriptional divergence patterns and characterized them with respect to coexpressed gene sets, chromosomal clustering of expression changes and functional gene categories. We directly compared observed transcriptional variation patterns in the mutation-accumulation and natural isolate lines to a neutral model of transcriptome evolution to show that strong stabilizing selection dominates the evolution of transcriptional change for thousands of C. elegans expressed sequences. An all pairs experiment design type is where all labeled extracts are compared to every other labeled extract. Keywords: all_pairs
2006-02-01 | GSE4123 | GEO
Project description:This set of arrays contains all microarray experiments done involving comparisons among C. elegans natural isolates and mutation-accumulation lines. Abstract: The evolutionary importance of gene-expression divergence is unclear: some studies suggest that it is an important mechanism for evolution by natural selection, whereas others claim that most between-species regulatory changes are neutral or nearly neutral. We examined global transcriptional divergence patterns in a set of Caenorhabditis elegans mutation-accumulation lines and natural isolate lines to provide insights into the evolutionary importance of transcriptional variation and to discriminate between the forces of mutation and natural selection in shaping the evolution of gene expression. We detected the effects of selection on transcriptional divergence patterns and characterized them with respect to coexpressed gene sets, chromosomal clustering of expression changes and functional gene categories. We directly compared observed transcriptional variation patterns in the mutation-accumulation and natural isolate lines to a neutral model of transcriptome evolution to show that strong stabilizing selection dominates the evolution of transcriptional change for thousands of C. elegans expressed sequences. An all pairs experiment design type is where all labeled extracts are compared to every other labeled extract. Computed
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