title: Altered dopamine homeostasis differentially affects mitochondrial voltage-dependent anion channels turnover.
abstract: Altered dopamine homeostasis plays a key role in the pathogenesis of Parkinson's disease. The generation of reactive oxygen species by spontaneous dopamine oxidation impairs mitochondrial function, causing in turn an enhancement of oxidative stress. Recent findings have highlighted the role of mitochondrial outer membrane proteins in the regulation of the correct disposal of damaged mitochondria. Here, we report the effect of altered dopamine homeostasis on the mitochondrial functionality in human neuroblastoma SH-SY5Y cells, a cellular model widely used to reproduce impaired dopamine homeostasis. We observed that dopamine significantly and relevantly reduces VDAC1 and VDAC2 levels without any change in the mRNA levels. Although mitochondria are depolarized by dopamine and mitochondrial calcium influx is reduced, dysfunctional mitochondria are not removed by mitophagy as it would be expected. Thus, alteration of dopamine homeostasis induces a mitochondrial depolarization not counteracted by the mitophagy quality control. As a consequence, the elimination of VDACs may contribute to the altered mitochondrial disposal in PD pathogenesis, thus enhancing the role of oxidative stress.
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
authors.affiliation: Department of Biomedical Sciences, University of Padova, Padova, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Mammucari
authors.affiliation: Division of Biomedical Research, Department of Theoretical and Applied Sciences, University of Insubria, Busto Arsizio, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: D'Agostino
authors.affiliation: Department of Biomedical Sciences, University of Padova, Padova, Italy; Institute of Neuroscience, National Council of Research, Padova, Italy.
authors.forename: Rosario
authors.initials: R
authors.lastname: Rizzuto
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. Electronic address: mauro.fasano@uninsubria.it.
authors.forename: Mauro
authors.initials: M
authors.lastname: Fasano
mesh_terms: D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D006706:Homeostasis; D006801:Humans; D053078:Membrane Potential, Mitochondrial; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology*; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D010084:Oxidation-Reduction; D012333:RNA, Messenger / Q000235:genetics; D017382:Reactive Oxygen Species; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D050995:Voltage-Dependent Anion Channel 1 / Q000235:genetics / Q000378:metabolism*; D050996:Voltage-Dependent Anion Channel 2 / Q000235:genetics / Q000378:metabolism*
chemical_list: D012333:RNA, Messenger; D017382:Reactive Oxygen Species; C494762:VDAC1 protein, human; C494765:VDAC2 protein, human; D050996:Voltage-Dependent Anion Channel 2; D050995:Voltage-Dependent Anion Channel 1; D002118:Calcium; D004298:Dopamine
keywords: Dopamine; Mitophagy; Neuroblastoma; Parkinson's disease; VDACs