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Huntington's disease (HD) is a progressive neurodegenerative disorder associated with mutant Huntingtin\u2010induced abnormalities in neuronal mitochondrial dynamics and quality control. Former studies suggest that the removal of defective mitochondria may be compromised in HD. Mitochondrial quality control (MQC) is a complex, well\u2010orchestrated pathway that can be compromised through mitophagy dysregulation or impairment in the mitochondria\u2010lysosomal axis. Another mitochondrial stress response is the generation of mitochondrial\u2010derived vesicles that fuse with the endolysosomal system and form multivesicular bodies that are extruded from cells as extracellular vesicles (EVs). In this work, we aimed to study the presence of mitochondrial components in human EVs and the relation to the dysfunction of both mitochondria and the autophagy pathway. We comprehensively characterized the mitochondrial and autophagy alterations in premanifest and manifest HD carriers and performed a proteomic and genomic EVs profile. We observed that manifest HD patients exhibit mitochondrial and autophagy impairment associated with enhanced EVs release. Furthermore, we detected mitochondrial DNA and proteins in EVs released by HD cells and in neuronal\u2010derived EVs including VDAC\u20101 and alpha and beta subunits of ATP synthase F1. HD\u2010extracellular vesicles transport higher levels of mitochondrial genetic material in manifest HD patients, suggesting an alternative pathway for the 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.<\/jats:p>","DOI":"10.1002\/jex2.65","type":"journal-article","created":{"date-parts":[[2022,10,14]],"date-time":"2022-10-14T10:56:19Z","timestamp":1665744979000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Defective mitochondria\u2010lysosomal axis enhances the release of extracellular vesicles containing mitochondrial DNA and proteins in Huntington's disease"],"prefix":"10.1002","volume":"1","author":[{"given":"Margarida","family":"Beatriz","sequence":"first","affiliation":[{"name":"CNC\u2010Center for Neuroscience and Cell Biology CIBB \u2010 Centre for Innovative Biomedicine and Biotechnology University of Coimbra  Coimbra Portugal"},{"name":"IIIUC\u2010Institute for Interdisciplinary Research University of Coimbra  Coimbra Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rita","family":"Vila\u00e7a","sequence":"additional","affiliation":[{"name":"CNC\u2010Center for Neuroscience and Cell Biology CIBB \u2010 Centre for Innovative Biomedicine and Biotechnology University of Coimbra  Coimbra Portugal"},{"name":"IIIUC\u2010Institute for Interdisciplinary Research University of Coimbra  Coimbra Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra I.","family":"Anjo","sequence":"additional","affiliation":[{"name":"CNC\u2010Center for Neuroscience and Cell Biology CIBB \u2010 Centre for Innovative Biomedicine and Biotechnology University of Coimbra  Coimbra Portugal"},{"name":"Multidisciplinary Institute of Ageing University of Coimbra  Coimbra Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno","family":"Manadas","sequence":"additional","affiliation":[{"name":"CNC\u2010Center for Neuroscience and Cell Biology CIBB \u2010 Centre for Innovative Biomedicine and Biotechnology University of Coimbra  Coimbra Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Janu\u00e1rio","sequence":"additional","affiliation":[{"name":"FMUC\u2010Faculty of Medicine University of Coimbra  Coimbra Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. Cristina","family":"Rego","sequence":"additional","affiliation":[{"name":"CNC\u2010Center for Neuroscience and Cell Biology CIBB \u2010 Centre for Innovative Biomedicine and Biotechnology University of Coimbra  Coimbra Portugal"},{"name":"FMUC\u2010Faculty of Medicine University of Coimbra  Coimbra Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2543-8821","authenticated-orcid":false,"given":"Carla","family":"Lopes","sequence":"additional","affiliation":[{"name":"CNC\u2010Center for Neuroscience and Cell Biology CIBB \u2010 Centre for Innovative Biomedicine and Biotechnology University of Coimbra  Coimbra Portugal"},{"name":"IIIUC\u2010Institute for Interdisciplinary Research University of Coimbra  Coimbra Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,10,14]]},"reference":[{"issue":"16","key":"e_1_2_9_2_1","doi-asserted-by":"crossref","first-page":"9042","DOI":"10.3390\/ijms22169042","article-title":"Targeting lysosomes to reverse hydroquinone\u2010induced autophagy defects and oxidative damage in human retinal pigment epithelial cells","volume":"22","author":"Abokyi S.","year":"2021","journal-title":"International Journal of Molecular Sciences"},{"issue":"4","key":"e_1_2_9_3_1","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1002\/pmic.201400221","article-title":"Short gelc\u2010SWATH: A fast and reliable quantitative approach for proteomic screenings","volume":"15","author":"Anjo S. 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