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.

Mitochondrial Damage-Associated Molecular Patterns Content in Extracellular Vesicles Promotes Early Inflammation in Neurodegenerative Disorders

“…Additionally, Todkar et al proposed that to prevent the secretion of oxidised proteins and consequent activation of the immune system, cells can selectively target ROSinduced mitochondrial proteins-containing EVs to lysosomes for degradation [166]. However, our lab recently showed that an impairment in the mitochondrial-lysosomal axis can promote the release of mitochondrial DAMPs in EVs [88]. Mitochondrial components can be secreted through the endocytic pathway and later be released into the extracellular space as EVs [175].…”

“…Importantly, in most neurodegenerative disorders, the inflammation is not driven by a pathogen, suggesting that neuroinflammation might be triggered by autologous molecules. Excessive mitochondrial damage associated to impaired mitophagy, commonly observed in neurodegenerative disorders [87], can lead to the release of mtDAMPs into the cytoplasm and extracellular environment, thus enhancing the neuroinflammatory process [88]. Moreover, sustained mitochondrial dysfunction leads to cell death which is aggravated in the central nervous system (CNS) due to the high metabolic demand and the limited capacity of neuronal regeneration [80].…”

“…Several studies have shown that mitochondrial components are secreted by cells under physiological and pathological conditions [88,[163][164][165]. Moreover, numerous mitochondrial proteins have been identified inside EVs such as TFAM, TOM20, CytC, PDH, mtHSP70 (mitochondrial matrix), NDUFA9 (mitochondrial Complex I subunit), SDHA (mitochondrial Complex II), UQCRC2 (mitochondrial Complex III), OPA1, ATP5A and VDAC1 [88,[166][167][168] identified several biological functions linked to extracellular mitochondria elements including restoration of mitochondrial function and metabolic rescue [164], mitochondrial degradation [169] and inflammation [85,166]. Mitochondria seems to play a role on the NLRP3 inflammasome [170].…”

“…A proteomic analysis of EVs content from AD brains (grey matter tissue from the frontal cortex) showed that 148 proteins were exclusive to the AD samples and were linked to mitochondrial function by Gene Ontology analysis [198]. In HD, TFAM was detected in HD human fibroblasts derived EVs [88] and CytC in human iPSC-derived neural stem cells EVs [137]. Besides mitochondrial proteins, mtDNA and mtDNA-RNA were identified in EVs [88,155,166,167,196,199].…”

“…In HD, TFAM was detected in HD human fibroblasts derived EVs [88] and CytC in human iPSC-derived neural stem cells EVs [137]. Besides mitochondrial proteins, mtDNA and mtDNA-RNA were identified in EVs [88,155,166,167,196,199]. Although EVs-associated mtDNA was shown to rescue oxidative phosphorylation deficits in breast cancer cells [167], the pro-inflammatory action of EV-related mtDNA has also been described [200].…”