title: Dopamine induces mitochondrial depolarization without activating PINK1-mediated mitophagy.
abstract: Parkinson's disease (PD) is one of the most prevalent neurodegenerative disorders, characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta. PD mostly occurs sporadically and its cause remains unknown, nevertheless the discovery of familiar forms of PD, characterized by mutations of genes encoding proteins associated with mitochondria homeostasis, suggests a strong implication of the mitochondrial quality control system in PD. We investigated the effect of dopamine cytosolic accumulation in undifferentiated SH-SY5Y cells, an in vitro model widely used to reproduce impairment of dopamine homeostasis, an early step in PD pathogenesis. A strong depolarization of the mitochondrial membrane was observed after dopamine exposure. Nevertheless, mitochondrial network resulted to assume a peculiar morphology with a distinct pattern of OPA1 and MFN1, key regulators of mitochondrial dynamics. Moreover, selective elimination of dysfunctional mitochondria did not take place, suggesting an impairment of the mitophagic machinery induced by dopamine. Indeed, PINK1 did not accumulate on the outer mitochondrial membrane, nor was parkin recruited to depolarized mitochondria. Altogether, our results indicate that an improper handling of dysfunctional mitochondria may be a leading event in PD pathogenesis. Impaired dopamine (DA) homeostasis and oxidative stress play a key role in the pathogenesis of Parkinson's disease. Free cytosolic dopamine undergoes spontaneous oxidation and generates semiquinonic and quinonic species (DAQ) with the concurrent production of reactive oxygen species (ROS). Dopamine dissipates mitochondrial potential (Δψm) with a peculiar alteration of the mitochondrial network. However, PINK1-dependent mitophagy is not activated by dopamine toxicity and dysfunctional mitochondria accumulate inside the cell.
authors.affiliation: Division of Biomedical Research, Department of Theoretical and Applied Sciences, University of Insubria, Busto Arsizio, Italy.|Center of Neuroscience, University of Insubria, Busto Arsizio, Italy.
authors.forename: Heather
authors.initials: H
authors.lastname: Bondi
authors.affiliation: Division of Biomedical Research, Department of Theoretical and Applied Sciences, University of Insubria, Busto Arsizio, Italy.|Center of Neuroscience, University of Insubria, Busto Arsizio, Italy.
authors.forename: Mara
authors.initials: M
authors.lastname: Zilocchi
authors.affiliation: Division of Biomedical Research, Department of Theoretical and Applied Sciences, University of Insubria, Busto Arsizio, Italy.
authors.forename: Maria Gabriella
authors.initials: MG
authors.lastname: Mare
authors.affiliation: Division of Biomedical Research, Department of Theoretical and Applied Sciences, University of Insubria, Busto Arsizio, Italy.|Biochemistry Unit, Second Department of Physiological Sciences, University of Barcelona, Barcelona, Spain.
authors.forename: Gianluca
authors.initials: G
authors.lastname: D'Agostino
authors.affiliation: Division of Biomedical Research, Department of Theoretical and Applied Sciences, University of Insubria, Busto Arsizio, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Giovannardi
authors.affiliation: Biochemistry Unit, Second Department of Physiological Sciences, University of Barcelona, Barcelona, Spain.
authors.forename: Santiago
authors.initials: S
authors.lastname: Ambrosio
authors.affiliation: Division of Biomedical Research, Department of Theoretical and Applied Sciences, University of Insubria, Busto Arsizio, Italy.|Center of Neuroscience, University of Insubria, Busto Arsizio, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Fasano
authors.affiliation: Division of Biomedical Research, Department of Theoretical and Applied Sciences, University of Insubria, Busto Arsizio, Italy.|Center of Neuroscience, University of Insubria, Busto Arsizio, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Alberio
keywords: PINK1; Parkinson's disease; dopamine; mitochondria; mitophagy; parkin