Defective mitochondria‐lysosomal axis enhances the release of extracellular vesicles containing mitochondrial DNA and proteins in Huntington's disease

Mitochondrial and autophagy dysfunction are mechanisms proposed to be involved in the pathogenesis of several neurodegenerative diseases. Huntington's disease (HD) is a progressive disorder associated with mutant Huntingtin-induced abnormalities neuronal mitochondrial dynamics quality control. Former studies suggest that removal defective mitochondria may compromised HD. control (MQC) complex, well-orchestrated pathway can through mitophagy dysregulation or impairment mitochondria-lysosomal axis. Another stress response generation mitochondrial-derived vesicles fuse endolysosomal system form multivesicular bodies extruded from cells as extracellular (EVs). In this work, we aimed study presence components human EVs relation both pathway. We comprehensively characterized alterations premanifest manifest HD carriers performed proteomic genomic profile. observed patients exhibit enhanced release. Furthermore, detected DNA proteins released by neuronal-derived including VDAC-1 alpha beta subunits ATP synthase F1. HD-extracellular transport higher levels genetic material patients, suggesting an alternative for secretion reactive components. This provides novel framework connecting release lysosomal