Overexpression of Mitochondrial Calcium Uniporter Causes Neuronal Death
Overexpression of Mitochondrial Calcium Uniporter Causes Neuronal Death
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DOI：
10.1155/2019/1681254
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发表时间：
2019-10-16
影响因子：
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通讯作者：
Rizzuto, Rosario
中科院分区：
文献类型：
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作者：
Granatiero, Veronica;Pacifici, Marco;Rizzuto, Rosario
神经退行性疾病是一大类异质性疾病，其特征是特定神经元亚型选择性和进行性死亡。在大多数情况下，尽管已经提出了许多假设，但其病理生理学仍然知之甚少。其中，Ca2+稳态失调和线粒体功能障碍代表了两个被广泛认可的与神经退行性疾病相关的早期事件。然而，可以在这两个假设之间建立直接联系。线粒体积极参与全局 Ca2+ 信号传导，已知细胞器基质内 [Ca2+] 的增加可维持能量产生，从而调节细胞凋亡和重塑胞质 Ca2+ 波。最重要的是，虽然线粒体 Ca2+ 超载被认为是不返回信号，会引发细胞凋亡或坏死性神经元死亡，但到目前为止，支持这一假设的直接证据（尤其是体内证据）仍然有限。在这里，我们利用线粒体 Ca2+ 单向转运蛋白 (MCU) 的鉴定，测试线粒体 Ca2+ 信号传导是否控制神经细胞的命运。我们在体外（小鼠原代皮层神经元）和体内（通过在大脑皮层中立体定向注射 MCU 编码腺病毒颗粒）过度表达 MCU。我们首先使用定量基因编码 Ca2+ 探针测量线粒体 Ca2+ 摄取，我们观察到 MCU 的过度表达导致静息时和膜去极化后线粒体 Ca2+ 摄取急剧增加。 MCU 介导的线粒体 Ca2+ 过载会导致细胞器形态的改变和整体 Ca2+ 稳态的失调。最重要的是，MCU 在体内的过度表达足以引发神经胶质增生和神经元损失。总体而言，我们证明线粒体 Ca2+ 超载本身足以在体外和体内引起神经元细胞死亡，从而突出了神经退行性变的潜在关键步骤。
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 Ca2+ 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 Ca2+ signaling, and increases of [Ca2+] inside organelle matrix are known to sustain energy production to modulate apoptosis and remodel cytosolic Ca2+ waves. Most importantly, while mitochondrial Ca2+ 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 Ca2+ uniporter (MCU) and tested whether mitochondrial Ca2+ 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 Ca2+ uptake using quantitative genetically encoded Ca2+ probes, and we observed that the overexpression of MCU causes a dramatic increase of mitochondrial Ca2+ uptake both at resting and after membrane depolarization. MCU-mediated mitochondrial Ca2+ overload causes alteration of organelle morphology and dysregulation of global Ca2+ homeostasis. Most importantly, MCU overexpression in vivo is sufficient to trigger gliosis and neuronal loss. Overall, we demonstrated that mitochondrial Ca2+ overload is per se sufficient to cause neuronal cell death both in vitro and in vivo, thus highlighting a potential key step in neurodegeneration.