Investigating the function of mitochondrial derived vesicles in neurons and their role in Parkinson's disease Rosalind Roberts, Thomas Durcan & Edward Fon Montreal Neurological Institute, McGill University
Mitochondrial quality control (QC) mechanisms have evolved to ensure the maintenance of a healthy mitochondrial population, which is essential for normal neuronal function. Mitochondrial-derived vesicles (MDVs) are a recently described mitochondrial QC mechanism, which we hypothesise is crucial for maintaining neuronal health and that functions aberrantly in Parkinson's disease (PD). Our lab recently demonstrated that PINK1 and Parkin, which are mutated in autosomal recessive forms of PD and whose canonical function is to mediate the removal of damaged mitochondria by autophagy (mitophagy), regulate the generation of a subtype of mitochondrial derived vesicles (MDVs) in response to oxidative stress. PINK1/Parkin-dependent MDVs shuttle damaged mitochondrial cargo to the lysosome for degradation. We hypothesise that MDVs are the first line of mitochondrial QC in neurons, eliminating damaged mitochondrial components before sufficient damage accrues to induce mitophagy. However, MDVs have not yet been studied in human neurons, which is crucial to understand the contribution of MDVs in maintaining mitochondrial health physiologically and particularly during the pathogenesis of PD. Utilizing human induced pluripotent stem cells (iPSCs) to differentiate neurons, we undertook to study MDVs for the first time in a human neuronal system. MDVs formed basally in cultures of different neuronal types (dopaminergic, cortical and motor neuronal cultures) and their generation was stimulated by oxidative stress following treatment with the complex III inhibitor, antimycin A. Culturing neurons in low glucose media potentiated the MDV response, in parallel with an augmented oxygen consumption rate, indicative of increased mitochondrial respiration and concomitant increased reactive oxygen species. These data suggest that MDV formation is an important mechanism to deal with oxidative stress in neurons. Future investigations will use PD patient iPSC-derived neurons to study whether the pathway is abrogated in diseased neurons. This work will provide new insights into the role of MDVs in mitochondrial QC in neurons and in PD.
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