Mitochondrial Calcium Cycling in Neuronal Function

描述（由申请人提供）：除了它们的生物能功能之外，线粒体是神经元中Ca信号传导的关键调节剂。线粒体有效地缓冲兴奋过程中的Ca 2+内流，并限制胞浆Ca 2+浓度（[Ca 2 +]i）增加的幅度。快速的Ca ~（2+）摄取后，线粒体缓慢释放Ca ~（2+），完成刺激诱导的线粒体Ca ~（2+）循环。通过塑造[Ca 2 +]i反应，线粒体可以调节许多Ca 2+依赖性神经元功能。与此同时，线粒体Ca 2+转运障碍是导致中风和许多神经退行性疾病中神经元损伤的关键因素。尽管取得了重大进展，许多问题仍然存在的时空组织，功能和调节的线粒体Ca 2+循环的神经元，特别是有关的机制，调节从生理学到病理生理学的转变。我们的总体假设是，线粒体Ca 2+循环控制不同的神经元功能和生理和病理结果之间的决定是由可逆的线粒体蛋白磷酸化的影响。我们将首先集中在两个生理过程，发射释放（目的1）和转录激活（目的2），通过研究时空组织和线粒体Ca 2+运输的作用，在两个形态和功能不同的细胞室，突触前扣和细胞索马，分别。然后，我们将研究蛋白激酶A和蛋白磷酸酶2A如何调节线粒体Ca 2+信号和Ca 2+依赖的过程，如神经传递，转录激活和兴奋性毒性（目的3）。这两种酶都靶向线粒体外膜（OMM），但对细胞存活表现出相反的作用，并预测差异影响线粒体依赖性功能。这些研究将促进我们对线粒体Ca 2+转运蛋白如何与神经元中的蛋白激酶和磷酸酶相互作用以触发特定生理或病理反应的理解。

DESCRIPTION (provided by applicant): In addition to their bioenergetic function, mitochondria are critical regulators of Ca signaling in neurons. Mitochondria efficiently buffer Ca2+ influx during excitation and limit the amplitude of the cytosolic Ca2+ concentration ([Ca2+]i) increase. Rapid Ca2+ uptake is followed by a slower Ca release from mitochondria, completing stimulus-induced mitochondrial Ca2+ cycle. By shaping [Ca2+]i response, mitochondria can modulate numerous Ca2+-dependent neuronal functions. At the same time, impairment of mitochondrial Ca2+ transport is the key factor leading to neuronal damage in stroke and in a number of neurodegenerative disorders. Despite significant progress, many questions remain about the spatiotemporal organization, function and modulation of mitochondrial Ca2+ cycling in neurons and, specifically, about the mechanisms regulating the transition from physiology to pathophysiology. Our overall hypothesis is that mitochondrial Ca2+ cycling controls diverse neuronal functions and that the decision between physiological and pathological outcomes is influenced by reversible phosphorylation of mitochondrial proteins. We will initially focus on two physiological processes, transmitter release (Aim 1) and activation of transcription (Aim 2), by studying spatiotemporal organization and the role of mitochondrial Ca2+ transport in two morphologically and functionally distinct cellular compartments, presynaptic boutons and the cell soma, respectively. We will then investigate how protein kinase A and protein phosphatase 2A modulate mitochondrial Ca2+ signaling and Ca2+-dependent processes, such as neurotransmission, transcription activation and excitotoxicity (Aim 3). Both enzymes are targeted to the outer mitochondrial membrane (OMM), but exhibit opposite effects on cell survival, and are predicted to differentially influence mitochondria-dependent functions. The proposed studies will advance our understanding of how mitochondrial Ca2+ transporters interplay with protein kinases and phosphatases in neurons to trigger a specific physiological or pathological response.