Overexpression of Mitochondrial Calcium Uniporter Causes Neuronal Death

Neurodegenerative diseases are a large and heterogeneous group of disorders characterized by selective and progressive death of specific neuronal subtypes. In most of the cases, the pathophysiology is still poorly understood, although a number of hypotheses have been proposed. Among these, dysregulation of Ca(2+) 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(2+) signaling, and increases of [Ca(2+)] inside organelle matrix are known to sustain energy production to modulate apoptosis and remodel cytosolic Ca(2+) waves. Most importantly, while mitochondrial Ca(2+) overload has been proposed as the no-return signal, triggering apoptotic or necrotic neuronal death, until now direct evidences supporting this hypothesis, especially in vivo, are limited. Here, we took advantage of the identification of the mitochondrial Ca(2+) uniporter (MCU) and tested whether mitochondrial Ca(2+) signaling controls neuronal cell fate. We overexpressed MCU both in vitro, in mouse primary cortical neurons, and in vivo, through stereotaxic injection of MCU-coding adenoviral particles in the brain cortex. We first measured mitochondrial Ca(2+) uptake using quantitative genetically encoded Ca(2+) probes, and we observed that the overexpression of MCU causes a dramatic increase of mitochondrial Ca(2+) uptake both at resting and after membrane depolarization. MCU-mediated mitochondrial Ca(2+) overload causes alteration of organelle morphology and dysregulation of global Ca(2+) homeostasis. Most importantly, MCU overexpression in vivo is sufficient to trigger gliosis and neuronal loss. Overall, we demonstrated that mitochondrial Ca(2+) overload is per se sufficient to cause neuronal cell death both in vitro and in vivo, thus highlighting a potential key step in neurodegeneration.