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. 2022 Aug 26;15:947191. doi: 10.3389/fnmol.2022.947191

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Copyright © 2022 Thorne and Tumbarello.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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Alterations in alpha-synuclein function may impact mitochondrial quality control pathways. Alpha-synuclein function and its aggregation may have an impact at multiple levels during both mitophagy and the mitochondrial-derived vesicle pathway. (1) MDV formation: Drp1 and Miro proteins are required for mitochondrial-derived vesicle (MDV) fission from the mitochondrion in response to local oxidative damage, which may be directly influenced by alterations in alpha-synuclein (α-syn) function. Alpha-synuclein oligomers can stabilize Miro on the mitochondrial membrane and modulate Drp1 localization, although the precise impact of alpha-synuclein-induced alterations in Drp1 function is still a point of contention (indicated in gray). (2) MDV trafficking: Oligomeric species of alpha-synuclein may downregulate Parkin expression and alter its localization, which could have negative impacts on MDV formation and trafficking to the lysosome. (3) Mitophagosome formation: Mitophagy requires the action of PINK1 and Parkin to trigger the ubiquitylation of outer membrane proteins which leads to the recruitment of autophagy receptors, including NDP52 and OPTN, which facilitate the capture of damaged mitochondria within a phagophore, which matures into a mitophagosome. Alpha-synuclein may impact this process through alterations in Parkin activity and by inhibiting the recruitment of Atg9-positive vesicles which are required for autophagosomal membrane expansion. (4) Mitophagosome trafficking: Through interactions with spectrin, overexpression and accumulation of alpha-synuclein oligomers alters actin cytoskeletal dynamics resulting in its aberrant stabilization, which may negatively impact the maturation and trafficking of mitophagosomes required for endosomal and lysosomal fusion. (5) Lysosomal fusion: To enable cargo degradation, the mitophagosome requires the action of SNARE protein complexes to facilitate lysosomal fusion. Pathogenic overexpression of alpha-synuclein may alter SNAP29 activity, thus influencing the ability of mitophagosomes to fuse with lysosomes. In addition, accumulation of monomeric and oligomeric species of alpha-synuclein within lysosomes alters their activity, which may result in negative impacts on cargo degradation in both the mitophagy and MDV pathways.