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The Impact of Mitochondrial Fusion and Fission Modulation in Sporadic Parkinson’s Disease

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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.

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Acknowledgments

Work in our laboratory is supported by funds from PTDC/SAU-NEU/102710/2008 to SM Cardoso. AR Esteves is supported by Post-Doctoral Fellowship, and D Santos and DF Silva are supported by PhD Fellowship from Portuguese Foundation for Science and Technology (FCT-MCTES, Portugal).

Author Contributions

SMC and DS conceived and designed the experiments; DS, ARE, and DFS performed the experiments; ARE and SMC analyzed the data; ARE and SMC wrote the paper; and CJ provided the PD patient samples.

Conflict of Interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. CNC – Centro de Neurociências e Biologia Celular, Universidade de Coimbra, Coimbra, Portugal

    Daniel Santos, A. Raquel Esteves, Diana F. Silva & Sandra M. Cardoso

  2. Hospitais da Universidade de Coimbra, 3000, Coimbra, Portugal

    Cristina Januário

  3. Faculdade de Medicina, Universidade de Coimbra, Coimbra, Portugal

    Sandra M. Cardoso

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  1. Daniel Santos
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  2. A. Raquel Esteves
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  3. Diana F. Silva
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  4. Cristina Januário
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  5. Sandra M. Cardoso
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Corresponding author

Correspondence to Sandra M. Cardoso.

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Supplementary Figure 1

Mitochondrial fragmentation in PD cells. Representative immunofluorescence pictures evidencing mitochondrial network in CT and PD Cybrids, under basal conditions, and in MPP+ or Nocodazole treated CT cybrids (1 mM, 24 h; 5 nM, 24 h). Immunostaining was performed using mitotracker green. PD cybrids mitochondrial network morphology is placed between the pronounced mitochondrial fragmentation and perinuclear distribution in MPP+-treated CT cybrids and the interconnected well distributed CT cybrids mitochondrial network. Green: Mitotracker green, Blue: Hoechst. (Magnification ×63). (GIF 1090 kb)

High resolution image (TIFF 1748 kb)

Supplementary Figure 2

Expression of mitochondrial fission/fusion proteins in PD cybrids. Representative immunoblot (a) and quantification analysis (b) revealed that MPP+ treatment of CT cybrids reduces the levels of the fusion protein Mfn2 and the phosphorylation of the fission protein Drp1 (Ser616). MPP+ also modulated the conversion of Opa1 long isoforms (LI) into short isoforms (SI) (C). Data represent mean ± SEM values derived from, at least, three independent determinations. * p < 0.05, *** p < 0.001, significantly different when compared to CT cybrid group. (GIF 1755 kb)

High resolution image (TIFF 1201 kb)

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Santos, D., Esteves, A.R., Silva, D.F. et al. The Impact of Mitochondrial Fusion and Fission Modulation in Sporadic Parkinson’s Disease. Mol Neurobiol 52, 573–586 (2015). https://doi.org/10.1007/s12035-014-8893-4

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