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In most of the cases, the pathophysiology is still poorly understood, although a number of hypotheses have been proposed. Among these, dysregulation of Ca\n                    <jats:sup>2+<\/jats:sup>\n                    homeostasis and mitochondrial dysfunction represent two broadly recognized early events associated with neurodegeneration. However, a direct link between these two hypotheses can be drawn. Mitochondria actively participate to global Ca\n                    <jats:sup>2+<\/jats:sup>\n                    signaling, and increases of [Ca\n                    <jats:sup>2+<\/jats:sup>\n                    ] inside organelle matrix are known to sustain energy production to modulate apoptosis and remodel cytosolic Ca\n                    <jats:sup>2+<\/jats:sup>\n                    waves. Most importantly, while mitochondrial Ca\n                    <jats:sup>2+<\/jats:sup>\n                    overload has been proposed as the no-return signal, triggering apoptotic or necrotic neuronal death, until now direct evidences supporting this hypothesis, especially\n                    <jats:italic>in vivo<\/jats:italic>\n                    , are limited. Here, we took advantage of the identification of the mitochondrial Ca\n                    <jats:sup>2+<\/jats:sup>\n                    uniporter (MCU) and tested whether mitochondrial Ca\n                    <jats:sup>2+<\/jats:sup>\n                    signaling controls neuronal cell fate. We overexpressed MCU both\n                    <jats:italic>in vitro<\/jats:italic>\n                    , in mouse primary cortical neurons, and\n                    <jats:italic>in vivo<\/jats:italic>\n                    , through stereotaxic injection of MCU-coding adenoviral particles in the brain cortex. We first measured mitochondrial Ca\n                    <jats:sup>2+<\/jats:sup>\n                    uptake using quantitative genetically encoded Ca\n                    <jats:sup>2+<\/jats:sup>\n                    probes, and we observed that the overexpression of MCU causes a dramatic increase of mitochondrial Ca\n                    <jats:sup>2+<\/jats:sup>\n                    uptake both at resting and after membrane depolarization. MCU-mediated mitochondrial Ca\n                    <jats:sup>2+<\/jats:sup>\n                    overload causes alteration of organelle morphology and dysregulation of global Ca\n                    <jats:sup>2+<\/jats:sup>\n                    homeostasis. Most importantly, MCU overexpression\n                    <jats:italic>in vivo<\/jats:italic>\n                    is sufficient to trigger gliosis and neuronal loss. Overall, we demonstrated that mitochondrial Ca\n                    <jats:sup>2+<\/jats:sup>\n                    overload is\n                    <jats:italic>per se<\/jats:italic>\n                    sufficient to cause neuronal cell death both\n                    <jats:italic>in vitro<\/jats:italic>\n                    and\n                    <jats:italic>in vivo<\/jats:italic>\n                    , thus highlighting a potential key step in neurodegeneration.\n                  <\/jats:p>","DOI":"10.1155\/2019\/1681254","type":"journal-article","created":{"date-parts":[[2019,10,16]],"date-time":"2019-10-16T19:30:22Z","timestamp":1571254222000},"page":"1-15","source":"Crossref","is-referenced-by-count":58,"title":["Overexpression of Mitochondrial Calcium Uniporter Causes Neuronal Death"],"prefix":"10.1155","volume":"2019","author":[{"given":"Veronica","family":"Granatiero","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences, University of Padova, Via Ugo Bassi 58B, Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Pacifici","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, University of Padova, Via Ugo Bassi 58B, Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8344-6459","authenticated-orcid":true,"given":"Anna","family":"Raffaello","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, University of Padova, Via Ugo Bassi 58B, Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3796-8907","authenticated-orcid":true,"given":"Diego","family":"De Stefani","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, University of Padova, Via Ugo Bassi 58B, Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7044-5097","authenticated-orcid":true,"given":"Rosario","family":"Rizzuto","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, University of Padova, Via Ugo Bassi 58B, Padova, 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