ArticleHuman molecular genetics2010
Dissecting the role of the mitochondrial chaperone mortalin in Parkinson's disease: functional impact of disease-related variants on mitochondrial homeostasis.
Article in Human molecular genetics, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 73 papers.
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73 citing papers in PubMed, 136 citations in OpenAlex.
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- Tryptoline Stereoprobe Elaboration Identifies Inhibitors of the GRPEL1-HSPA9 Chaperone Complex.bioRxiv : the preprint server for biology · 2025Article
- Whole organism and tissue-specific analysis of pexophagy inOpen biology · 2025Article
- Peroxisome dynamics and inter-organelle interactions in neuronal health and disease.Frontiers in molecular neuroscience · 2025Review
- Quantum chemistry rules retinoid biology.Communications biology · 2023Review
- Mortalin/Hspa9 involvement and therapeutic perspective in Parkinson's disease.Neural regeneration research · 2023Review
- PolyGA targets the ER stress-adaptive response by impairing GRP75 function at the MAM in C9ORF72-ALS/FTD.Acta neuropathologica · 2022Article
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- Analysis of Huntington's Disease Modifiers Using the Hyperbolic Mapping of the Protein Interaction Network.International journal of molecular sciences · 2022Article
- Altered Mitochondrial Protein Homeostasis and Proteinopathies.Frontiers in molecular neuroscience · 2022Review
- Exosome mediated Tom40 delivery protects against hydrogen peroxide-induced oxidative stress by regulating mitochondrial function.PloS one · 2022Article
- Insights Into the Role of Mortalin in Alzheimer's Disease, Parkinson's Disease, and HIV-1-Associated Neurocognitive Disorders.Frontiers in cell and developmental biology · 2022Review
- Cytoplasmic Polyadenylation Element-Binding Protein 1 Post-transcriptionally Regulates Fragile X Mental Retardation 1 Expression Through 3' Untranslated Region in Central Nervous System Neurons.Frontiers in cellular neuroscience · 2022Article
- Loss of Function of mtHsp70 Chaperone Variants Leads to Mitochondrial Dysfunction in Congenital Sideroblastic Anemia.Frontiers in cell and developmental biology · 2022Article
- Autophagy inhibition rescues structural and functional defects caused by the loss of mitochondrial chaperoneAutophagy · 2021Article
- HSPA9/Mortalin mediates axo-protection and modulates mitochondrial dynamics in neurons.Scientific reports · 2021Article
- Mitochondrial HSP70 Chaperone System-The Influence of Post-Translational Modifications and Involvement in Human Diseases.International journal of molecular sciences · 2021Review
- Review
- Mitochondrial Protein Import Dysfunction in Pathogenesis of Neurodegenerative Diseases.Molecular neurobiology · 2021Review
- Mitochondrial Chaperones and Proteases in Cardiomyocytes and Heart Failure.Frontiers in molecular biosciences · 2021Review
13 more citing papers are in PubMed but not listed here.
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Authors and funding
15 authors at 7 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The mitochondrial chaperone mortalin has been linked to neurodegeneration in Parkinson's disease (PD) based on reduced protein levels in affected brain regions of PD patients and its interaction with the PD-associated protein DJ-1. Recently, two amino acid exchanges in the ATPase domain (R126W) and the substrate-binding domain (P509S) of mortalin were identified in Spanish PD patients. Here, we identified a separate and novel variant (A476T) in the substrate-binding domain of mortalin in German PD patients. To define a potential role as a susceptibility factor in PD, we characterized the functions of all three variants in different cellular models. In vitro import assays revealed normal targeting of all mortalin variants. In neuronal and non-neuronal human cell lines, the disease-associated variants caused a mitochondrial phenotype of increased reactive oxygen species and reduced mitochondrial membrane potential, which were exacerbated upon proteolytic stress. These functional impairments correspond with characteristic alterations of the mitochondrial network in cells overexpressing mutant mortalin compared with wild-type (wt), which were confirmed in fibroblasts from a carrier of the A476T variant. In line with a loss of function hypothesis, knockdown of mortalin in human cells caused impaired mitochondrial function that was rescued by wt mortalin, but not by the variants. Our genetic and functional studies of novel disease-associated variants in the mortalin gene define a loss of mortalin function, which causes impaired mitochondrial function and dynamics. Our results support the role of this mitochondrial chaperone in neurodegeneration and underscore the concept of impaired mitochondrial protein quality control in PD.
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