SS-31 Reverses Mitochondrial Fragmentation in Fibroblasts from Patients with DCMA, a Mitochondrial Cardiomyopathy
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ABSTRACT:
PROVIDER: PRJNA552466 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR9640050.fastq.gz | Fastqsanger.gz | |||
| SRR9640051.fastq.gz | Fastqsanger.gz | |||
| SRR9640052.fastq.gz | Fastqsanger.gz | |||
| SRR9640053.fastq.gz | Fastqsanger.gz | |||
| SRR9640054.fastq.gz | Fastqsanger.gz |
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Project description:We used patient dermal fibroblasts to characterize the mitochondrial abnormalities associated with the dilated cardiomyopathy with ataxia syndrome (DCMA) and to study the effect of the mitochondrially-targeted peptide SS-31 as a potential novel therapeutic.
2019-07-04 | GSE133754 | GEO
Project description:We used patient dermal fibroblasts to characterize the mitochondrial abnormalities associated with the dilated cardiomyopathy with ataxia syndrome (DCMA) and to study the effect of the mitochondrially-targeted peptide SS-31 as a potential novel therapeutic. DCMA is a rare and understudied autosomal recessive disorder thought to be related to Barth syndrome but caused by mutations in DNAJC19, a protein of unknown function localized to the mitochondria. The clinical disease is characterized by 3-methylglutaconic aciduria, dilated cardiomyopathy, abnormal neurological development, and other heterogeneous features. Until recently no effective therapies had been identified and affected patients frequently died in early childhood from intractable heart failure. Skin fibroblasts from four pediatric patients with DCMA were used to establish parameters of mitochondrial dysfunction. Mitochondrial structure, reactive oxygen species (ROS) production, cardiolipin composition, and gene expression were evaluated. Immunocytochemistry with semi-automated quantification of mitochondrial structural metrics and transmission electron microscopy demonstrated mitochondria to be highly fragmented in DCMA fibroblasts compared to healthy control cells. Live-cell imaging demonstrated significantly increased ROS production in patient cells. These abnormalities were reversed by treating DCMA fibroblasts with SS-31, a synthetic peptide that localizes to the inner mitochondrial membrane. Levels of cardiolipin were not significantly different between control and DCMA cells and were unaffected by SS-31 treatment. Our results demonstrate the abnormal mitochondria in fibroblasts from patients with DCMA and suggest that SS-31 may represent a potential therapy for this devastating disease.
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Project description:SS-31 is a synthetic peptide that improves mitochondrial function and is currently undergoing clinical trials for treatments of heart failure, primary mitochondrial myopathy, and other mitochondrial diseases. SS-31 interacts with cardiolipin which is abundant in the inner mitochondrial membrane, but mechanistic details of its pharmacological effects are unknown. Here we apply a chemical cross-linking/mass spectrometry method to provide direct evidence for specific interactions between SS-31 and mitochondrial proteins. The identified SS-31 interactors are functional components in ATP production and 2-oxoglutarate metabolism and signaling, consistent with improved mitochondrial function resultant from SS-31 treatment. These results offer a glimpse of the protein interaction landscape of SS-31 and provide mechanistic insight relevant to SS-31 mitochondrial therapy
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Project description:Primary mitochondrial disease (PMD) patients manifesting cardiomyopathy are twice as likely to die as other PMD patients. One PMD with cardiomyopathy is caused by null mutations in the heart-muscle isoform of the adenine nucleotide translocator (ANT1) gene, the severity of the cardiomyopathy being mediated by the mitochondrial DNA (mtDNA). To perfect strategies for addressing mitochondria cardiomyopathy, we generated an Ant1 null mouse and combined it with our ND6P25L mtDNA mutation to mimic the hypertrophic versus dilated cardiomyopathies observed in patients, respectively. We then transduced the neonatal Ant1-/- and Ant1-/-+ND6P25L mouse hearts with an AAV9-pDesmin-GFP-Ant1 cDNA vector. Restoration of just 10% Ant1 gene expression was sufficient to ameliorate the cardiomyopathies in these mice. Proteomics and single nucleus RNA sequencing (snRNA-seq) revealed the reversal of dysregulated mitochondrial metabolic genes including PGC1α as well as cardiac contractile and extracellular matrix proteins. Hence, modest increase in cardiac mitochondrial energetics can have profound benefits on cardiac function and is effective in treating mitochondrial cardiomyopathy.
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