PloS one, 2010-02, Vol.5 (2), p.e9367-e9367
2010
Details
- Autor(en) / Beteiligte
- Titel
- Reduced basal autophagy and impaired mitochondrial dynamics due to loss of Parkinson's disease-associated protein DJ-1
- Ist Teil von
- PloS one, 2010-02, Vol.5 (2), p.e9367-e9367
- Ort / Verlag
- United States: Public Library of Science
- Erscheinungsjahr
- 2010
- Link zum Volltext
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- Mitochondrial dysfunction and degradation takes a central role in current paradigms of neurodegeneration in Parkinson's disease (PD). Loss of DJ-1 function is a rare cause of familial PD. Although a critical role of DJ-1 in oxidative stress response and mitochondrial function has been recognized, the effects on mitochondrial dynamics and downstream consequences remain to be determined. Using DJ-1 loss of function cellular models from knockout (KO) mice and human carriers of the E64D mutation in the DJ-1 gene we define a novel role of DJ-1 in the integrity of both cellular organelles, mitochondria and lysosomes. We show that loss of DJ-1 caused impaired mitochondrial respiration, increased intramitochondrial reactive oxygen species, reduced mitochondrial membrane potential and characteristic alterations of mitochondrial shape as shown by quantitative morphology. Importantly, ultrastructural imaging and subsequent detailed lysosomal activity analyses revealed reduced basal autophagic degradation and the accumulation of defective mitochondria in DJ-1 KO cells, that was linked with decreased levels of phospho-activated ERK2. We show that loss of DJ-1 leads to impaired autophagy and accumulation of dysfunctional mitochondria that under physiological conditions would be compensated via lysosomal clearance. Our study provides evidence for a critical role of DJ-1 in mitochondrial homeostasis by connecting basal autophagy and mitochondrial integrity in Parkinson's disease.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1932-6203eISSN: 1932-6203DOI: 10.1371/journal.pone.0009367Titel-ID: cdi_plos_journals_1289251150
- Format
- –
- Schlagworte
- Accumulation, Aging, Alzheimer's disease, Animal models, Animals, Apoptosis, Autophagy, Blotting, Western, Brain research, Cell Biology, Cell culture, Cell death, Degradation, Electron transport, Fibroblasts, Fibroblasts - cytology, Fibroblasts - metabolism, Fibroblasts - ultrastructure, Genes, Genetic aspects, Homeostasis, Humans, Hypoxia, Integrity, Intracellular Signaling Peptides and Proteins - genetics, Intracellular Signaling Peptides and Proteins - metabolism, Kinases, Laboratories, Lysosomes, Lysosomes - metabolism, Lysosomes - ultrastructure, Membrane potential, Mice, Mice, Knockout, Microscopy, Electron, Mitochondria, Mitochondria - metabolism, Mitogen-Activated Protein Kinase 1 - metabolism, Movement disorders, Mutation, Neurodegeneration, Neurodegenerative diseases, Neurological Disorders, Neurology, Neuroscience, Niso, Oncogene Proteins - genetics, Oncogene Proteins - metabolism, Organelles, Oxidative Phosphorylation, Oxidative stress, Oxygen, PARK7 protein, Parkinson Disease - genetics, Parkinson Disease - pathology, Parkinson's disease, Penicillin, Peroxiredoxins, Phagocytosis, Phosphorylation, Physiology, Protein Deglycase DJ-1, Proteins, Reactive oxygen species, Reactive Oxygen Species - metabolism, Respiration