Objective: To provide an overview of the current knowledge on alpha-synuclein (αS) interactions with mitochondrial quality control (MQC) pathways in Parkinson’s disease (PD).

Background: The maintenance of healthy mitochondria is essential for neuronal survival and relies upon MQC pathways: mitochondrial biogenesis, dynamics, and autophagy. As mitochondrial dysfunction is critically implicated in PD, dysfunctional MQC may be central to PD pathology. Also at the heart of PD is αS, which forms PD’s hallmark Lewy bodies. Though many studies have examined mitochondria and αS, the mechanisms through which αS may influence MQC are not fully understood. Understanding these interactions may be essential to elucidating PD pathogenesis.

Method: A literature search was performed using PubMed to identify published studies on αS and MQC. The search was restricted to studies published in English. Titles and abstracts of search results were also screened for relevance.

Results: In mitochondrial biogenesis, αS may directly bind to PGC-1α’s promoter sequence, repressing PGC-1α’s normal function in regulating mitochondrial biogenesis. An excess of exogenous αS was also shown to interfere with Parkin’s degradation of PARIS, thus increasing PARIS-mediated transcriptional repression of PGC-1α. 

In mitochondrial fusion dynamics, overexpression of pathogenic αS may increase cleavage of the fusion protein OPA1, inducing mitochondrial fragmentation. In mitochondrial fission, αS may interact directly with mitochondrial membranes, as well as increase translocation of DRP1, a key fission protein, to mitochondria.

In mitochondrial autophagy, overexpressed αS may stabilize Miro proteins, interfering with the formation of mitochondrial-derived vesicles (MDVs) and delaying mitophagy initiation. αS may also reduce Parkin levels, negatively impacting MDV trafficking and autophagosome formation. By binding to spectrin, αS may excessively stabilize the actin cytoskeleton, disrupting autophagosome trafficking. Lastly, overexpressed αS may decrease SNAP29 activity, affecting the SNARE complex that mediates autophagosome-lysosome fusion.

Conclusion: There is yet to be widespread consensus on αS’s influence on MQC in PD, and future research is necessary to fully understand these mechanisms. Additionally, most research on αS and MQC has used overexpressed or pathological αS. Examining endogenous αS and MQC may provide further insight into αS’s influence on MQC.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/alpha-synuclein-and-mitochondria-quality-control-in-parkinsons-disease-a-literature-review/