title: The Impact of Mitochondrial Fusion and Fission Modulation in Sporadic Parkinson's Disease.
abstract: Accumulating data suggests that mitochondrial deficits may underline both sporadic and familial Parkinson's disease (PD) neurodegenerative process. Impairment of mitochondrial dynamics results in reactive oxygen species (ROS) production, decreases mitochondrial membrane potential, and could potentiate the accumulation of dysfunctional mitochondria. Excessive mitochondrial fragmentation is associated with the pathology of sporadic PD. Therefore, we modulated mitochondria fusion and fission in different sporadic PD cellular models. We found alterations in two proteins known to regulate mitochondrial fusion and fission events (OPA1 and Drp1, respectively). OPA1 long isoform cleavage seems to be, at least in part, responsible for mitochondrial fragmented pattern observed in sporadic PD cellular models. Moreover, mitochondrial fragmentation can also occur due to an increase in Drp1 that is translocated into the mitochondria by phosphorylation. To disclose the relevance of these alterations to the fragmentation of the mitochondrial network, we overexpressed OPA1 and knock down Drp1. OPA1 overexpression did not rescue MPP(+)-induced increase in ROS. Nevertheless, Drp1 knockdown due to an increase in mitochondrial elongation and interconnectivity rescued mitochondrial membrane potential and decreased ROS production in sporadic PD cells. Overall, our findings suggest that Drp1-dependent mitochondrial fragmentation plays a crucial role in mediating mitochondrial DNA induced mitochondria abnormalities and cellular dysfunction in sporadic PD.
authors.affiliation: CNC - Centro de Neurociências e Biologia Celular, Universidade de Coimbra, Coimbra, Portugal.
authors.forename: Daniel
authors.initials: D
authors.lastname: Santos
authors.forename: A Raquel
authors.initials: AR
authors.lastname: Esteves
authors.forename: Diana F
authors.initials: DF
authors.lastname: Silva
authors.forename: Cristina
authors.initials: C
authors.lastname: Januário
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Cardoso
mesh_terms: D004272:DNA, Mitochondrial / Q000378:metabolism; D034281:Dynamins / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000378:metabolism; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D063154:Mitochondrial Dynamics; D010300:Parkinson Disease / Q000378:metabolism* / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D004272:DNA, Mitochondrial; D017382:Reactive Oxygen Species; D020558:GTP Phosphohydrolases; C415198:OPA1 protein, human; D034281:Dynamins