title: α-Synuclein controls mitochondrial calcium homeostasis by enhancing endoplasmic reticulum-mitochondria interactions.
abstract: α-Synuclein has a central role in Parkinson disease, but its physiological function and the mechanism leading to neuronal degeneration remain unknown. Because recent studies have highlighted a role for α-synuclein in regulating mitochondrial morphology and autophagic clearance, we investigated the effect of α-synuclein in HeLa cells on mitochondrial signaling properties focusing on Ca(2+) homeostasis, which controls essential bioenergetic functions. By using organelle-targeted Ca(2+)-sensitive aequorin probes, we demonstrated that α-synuclein positively affects Ca(2+) transfer from the endoplasmic reticulum to the mitochondria, augmenting the mitochondrial Ca(2+) transients elicited by agonists that induce endoplasmic reticulum Ca(2+) release. This effect is not dependent on the intrinsic Ca(2+) uptake capacity of mitochondria, as measured in permeabilized cells, but correlates with an increase in the number of endoplasmic reticulum-mitochondria interactions. This action specifically requires the presence of the C-terminal α-synuclein domain. Conversely, α-synuclein siRNA silencing markedly reduces mitochondrial Ca(2+) uptake, causing profound alterations in organelle morphology. The enhanced accumulation of α-synuclein into the cells causes the redistribution of α-synuclein to localized foci and, similarly to the silencing of α-synuclein, reduces the ability of mitochondria to accumulate Ca(2+). The absence of efficient Ca(2+) transfer from endoplasmic reticulum to mitochondria results in augmented autophagy that, in the long range, could compromise cellular bioenergetics. Overall, these findings demonstrate a key role for α-synuclein in the regulation of mitochondrial homeostasis in physiological conditions. Elevated α-synuclein expression and/or eventually alteration of the aggregation properties cause the redistribution of the protein within the cell and the loss of modulation on mitochondrial function.
authors.affiliation: Department of Comparative Biomedicine and Food Science, University of Padova, Padova, Italy.
authors.forename: Tito
authors.initials: T
authors.lastname: Calì
authors.forename: Denis
authors.initials: D
authors.lastname: Ottolini
authors.forename: Alessandro
authors.initials: A
authors.lastname: Negro
authors.forename: Marisa
authors.initials: M
authors.lastname: Brini
mesh_terms: D001483:Base Sequence; D002118:Calcium / Q000378:metabolism*; D045744:Cell Line, Tumor; D017931:DNA Primers; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D034741:RNA, Small Interfering / Q000235:genetics; D013347:Subcellular Fractions / Q000378:metabolism; D051844:alpha-Synuclein / Q000502:physiology*
chemical_list: D017931:DNA Primers; D034741:RNA, Small Interfering; D051844:alpha-Synuclein; D002118:Calcium