Dose-dependent CHCHD10 dysregulation affects motor neuron disease severity and creatine metabolism
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1157393 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| SRR30559852.fastq.gz | Fastqsanger.gz | |||
| SRR30559853.fastq.gz | Fastqsanger.gz | |||
| SRR30559854.fastq.gz | Fastqsanger.gz | |||
| SRR30559856.fastq.gz | Fastqsanger.gz |
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Project description:Dominant defects in CHCHD10, a mitochondrial intermembrane space protein, lead to a range of neurological and muscle phenotypes including amyotrophic lateral sclerosis. Many patients present with spinal muscular atrophy Jokela type (SMAJ), which is caused by a heterozygous p.G66V variant. While most disease variants lead to aggregation of CHCHD10 and activation of proteotoxic stress responses, the pathogenic mechanisms of the p.G66V variant have been less investigated. We report here the first homozygous CHCHD10 patient, with variant p.G66V. We compare the metabolic findings in heterozygous and homozygous SMAJ patient skin fibroblasts, and in motor neurons differentiated from patient-specific stem cells as well as a novel mouse model of SMAJ. Our findings show that p.G66V variant leads to dose-depended reduction of the CHCHD10 protein in a cell type specific manner. In addition, CHCHD10 p.G66V dysregulates energy metabolism, leading to altered redox balance and energy buffering by creatine metabolism.
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Project description:The motor neuron (MN)–hexamer complex consisting of LIM homeobox 3, Islet-1, and nuclear LIM interactor is a key determinant of motor neuron specification and differentiation. To gain insights into the transcriptional network in motor neuron development, we performed a genome-wide ChIP-sequencing analysis and found that the MN–hexamer directly regulates a wide array of motor neuron genes by binding to the HxRE (hexamer response element) shared among the target genes. Interestingly, STAT3-binding motif is highly enriched in the MN–hexamer–bound peaks in addition to the HxRE. We also found that a transcriptionally active form of STAT3 is expressed in embryonic motor neurons and that STAT3 associates with the MN–hexamer, enhancing the transcriptional activity of the MN–hexamer in an upstream signal-dependent manner. Correspondingly, STAT3 was needed for motor neuron differentiation in the developing spinal cord. Together, our studies uncover crucial gene regulatory mechanisms that couple MN–hexamer and STAT-activating extracellular signals to promote motor neuron differentiation in vertebrate spinal cord. To explain our experimental scheme briefly, we are interested in finding target sites for the dimer of transcription factors Isl1 and Lhx3. To mimic the biological activity of Isl1/Lhx3 dimer, we made Isl1-Lhx3 fusion and found that Isl1-Lhx3 has a potent biological activity in multiple systems (i.e. generation of ectopic motor neurons). Then we made ES cell line that induces Flag-tagged Isl1-Lhx3 expression upon Dox treatment. These *mouse* ES cells differentiate to motor neurons (iMN-ESCs) when treated with Dox following EB formation. To identify genomic binding sites of Isl1-Lhx3 (Flag-tagged), we performed ChIP with Flag antibody (pull down of Flag-Isl1-Lhx3) in ES cells treated with Dox. ChIP with Flag antibody in ES cells treated with vehicle (no Dox) was done as a negative control in parallel, and sequenced along with +Dox sample. We have done these experiments twice (two sets).
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Project description:Mutations in CHCHD10, a mitochondrial protein implicated in proteostasis and cristae maintenance, cause autosomal dominant mitochondrial diseases characterized by cardiomyopathy and neurodegeneration. Heterozygous Chchd10 S55L knock-in mice (modeling the human S59L variant) develop progressive mitochondrial cardiomyopathy driven by CHCHD10 aggregation, which is associated with chronic activation of the mitochondrial integrated stress response (mtISR). Here, we demonstrate that cardiac dysfunction is affected by biological sex and is associated with dual defects originating at the onset of disease: (1) early respiratory chain failure linked to cytochrome c depletion and impaired copper homeostasis and (2) maladaptive mtISR signaling via the OMA1-DELE1-HRI axis. Genetic inactivation of OMA1 delays cardiomyopathy without rescuing CHCHD10 insolubility, proteomic remodeling, cristae defects or OXPHOS impairment, demonstrating that mtISR can be uncoupled from the bioenergetic collapse triggered by CHCHD10 protein aggregation. Proteomic profiling of soluble and insoluble mitochondrial proteins reveals wide-spread disruptions of mitochondrial proteostasis, including IMS proteins involved in cytochrome c biogenesis. Defective respiration in mutant mitochondria could be rescued by the exogenous addition of cytochrome c, pinpointing IMS proteostasis disruption as a key pathogenic mechanism. Our work reveals that CHCHD10 insolubility and aggregation compromises metabolic resilience by impairing both electron transport and stress adaptation within the IMS, offering new perspectives for the development of therapeutic targets. This repository contains the heart whole proteome of the four different genotypes. a) whole proteome dataset is indicated by the identifier: KmUUbGabck
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Project description:To determine what kind of genes are involved in vocal learning ability, we performed microarray experiments using 3 vocal learning species (zebra finch, budgerigar, Anna's hummingbird) and 2 non-vocal learning species(ring dive, and Japanese quail) from the bird group. All of the animals are male adults. They were isolated over night and had 1hour light exposure at morning. Birds who did not sing were used in this experiment. We used 2-3 animals each species. We used the 12th motor neuron for both vocal learners and non-vocal learners. We used the Supra Spinal motor neuron (ssp) as control area for both groups.
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Project description:Mutations in CHCHD10, a mitochondrial protein with undefined functions, are associated with autosomal dominant mitochondrial diseases. Chchd10 knock-in mice harboring a heterozygous S55L mutation (equivalent to human pathogenic S59L) develop a fatal mitochondrial cardiomyopathy caused by CHCHD10 aggregation and proteotoxic mitochondrial integrated stress response (mtISR). In mutant hearts, mtISR is accompanied by a metabolic rewiring characterized by increased reliance on glycolysis rather than fatty acid oxidation. To counteract this metabolic rewiring, heterozygous S55L mice were subjected to chronic high fat diet (HFD) to decrease insulin sensitivity and glucose uptake and enhance fatty acid utilization in the heart. HFD ameliorated the ventricular dysfunction of mutant hearts and significantly extended the survival of mutant female mice affected by severe pregnancy-induced cardiomyopathy. Gene expression profiles confirmed that HFD increased fatty acid utilization and ameliorated cardiomyopathy markers. Importantly, HFD also decreased accumulation of aggregated CHCHD10 in the S55L heart, suggesting activation of quality control mechanisms. Overall, our findings indicate that metabolic therapy can be effective in mitochondrial cardiomyopathies associated with proteotoxic stress.
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