Defective mitochondrial-lysosomal axis promotes extracellular vesicles release of mitochondrial components in Huntington’s Disease
Defective mitochondrial-lysosomal axis promotes extracellular vesicles release of mitochondrial components in Huntington’s Disease
ABSTRACT Mitochondrial and autophagy dysfunction are mechanisms proposed to be involved in the pathogenesis of several neurodegenerative diseases. Huntington’s disease (HD) is a progressive neurodegenerative disorder associated with mutant Huntingtin-induced abnormalities in neuronal mitochondrial dynamics and quality control. Former studies suggest that the removal of defective mitochondria may be compromised in HD. The mitochondrial quality control is a complex, well-orchestrated pathway that can be compromised through mitophagy dysregulation or impairment in the mitochondrial-lysosomal axis. Another mitochondrial stress response is the generation of mitochondrial-derived vesicles that fuse with the endolysosomal system and form multivesicular bodies that are extruded from cells as extracellular vesicles (EVs). In this study, we comprehensively characterized the mitochondrial and autophagy alterations in premanifest and manifest HD patients and performed a proteomic and genomic EVs profile. We observed that manifest HD patients exhibit mitochondrial and autophagy impairment associated with enhanced EVs release. Further, we detected mitochondrial components in EVs released by HD cells and in neuron-derived EVs. The EV-associated mtDNA copies were elevated in manifest HD patients suggesting to be an alternative pathway for secretion of reactive mitochondrial components. This study provides a novel framework connecting EVs enhanced release of mitochondrial components to mitochondrial and lysosomal dysfunction in HD.
Rego A. Cristina、Lopes Carla、Anjo Sandra I.、Beatriz Margarida、Janu¨￠rio Cristina、Vila?a Rita、Manadas Bruno
CNC-Center for Neuroscience and Cell Biology, CIBB - Centre for Innovative Biomedicine and Biotechnology, University of Coimbra||FMUC-Faculty of Medicine, University of CoimbraCNC-Center for Neuroscience and Cell Biology, CIBB - Centre for Innovative Biomedicine and Biotechnology, University of Coimbra||IIIUC-Institute for Interdisciplinary Research, University of CoimbraCNC-Center for Neuroscience and Cell Biology, CIBB - Centre for Innovative Biomedicine and Biotechnology, University of Coimbra||Multidisciplinary Institute of Ageing, University of CoimbraCNC-Center for Neuroscience and Cell Biology, CIBB - Centre for Innovative Biomedicine and Biotechnology, University of Coimbra||IIIUC-Institute for Interdisciplinary Research, University of CoimbraFMUC-Faculty of Medicine, University of CoimbraCNC-Center for Neuroscience and Cell Biology, CIBB - Centre for Innovative Biomedicine and Biotechnology, University of Coimbra||IIIUC-Institute for Interdisciplinary Research, University of CoimbraCNC-Center for Neuroscience and Cell Biology, CIBB - Centre for Innovative Biomedicine and Biotechnology, University of Coimbra
神经病学、精神病学基础医学分子生物学
Huntington’s diseasemitochondrial dysfunctionautophagyextracellular vesiclesmitochondrial DNAneuronal-derived extracellular vesicles
Rego A. Cristina,Lopes Carla,Anjo Sandra I.,Beatriz Margarida,Janu¨￠rio Cristina,Vila?a Rita,Manadas Bruno.Defective mitochondrial-lysosomal axis promotes extracellular vesicles release of mitochondrial components in Huntington’s Disease[EB/OL].(2025-03-28)[2025-05-04].https://www.biorxiv.org/content/10.1101/2022.02.13.480262.点此复制
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