MITOCHONDRIAL DYSFUNCTION IN THE BRAIN ALTERS THE HOMEOSTASIS OF A NEWLY IDENTIFIED POPULATION OF MITOCHONDRIA-DERIVED EXTRACELLULAR VESICLES
- Pasquale D'Acunzo, United States of America
Abstract
Aims
Mitochondrial damage and oxidative stress are well-established players in the pathophysiology of several neurodegenerative diseases, including Parkinson’s disease, Alzheimer’s disease, and Down syndrome (DS). Using a novel high-resolution density step-gradient to isolate and fractionate subpopulations of extracellular vesicles (EVs) from the brain parenchyma, we investigated the effect of mitochondrial dysfunction on the number and content of EVs in DS brains.
Methods
We isolated EVs from murine and human DS and diploid control post-mortem brains or from cell media. EVs were analyzed by nanoparticle tracking analysis, cryogenic electron microscopy, Western blotting, mass spectrometry, and qPCR.
Results
We found that the extracellular matrix of the brain contains a newly identified population of metabolically active, double-membrane, electron-dense EVs of mitochondrial origin that we have named ‘mitovesicles’. In vitro study revealed that oxidative stress enhances mitovesicle release in a mitophagy-independent fashion. In wild-type brains, we revealed that mitovesicles are low in number and encapsulate a specialized subset of mitochondrial constituents that reflects only partially the composition of intracellular mitochondria. Conversely, in human and murine DS brains, mitovesicle number is higher when compared to controls. The content is also modified, as the amount of the pro-inflammatory mitochondrial DNA in mitovesicles was higher in DS compared to controls.
Conclusions
Brain mitovesicles are tightly regulated in normal conditions and are modified in DS, suggesting that mitovesicles are a previously unrecognized player in mitochondria quality control and may have a yet undiscovered role in the inter-cellular response to oxidative stress and neuroinflammation.