Mitochondria and metabolism in neurodegeneration

总结 目前，约有580万美国人患有阿尔茨海默病（AD）1， 治疗以减轻相关的神经元功能障碍和细胞死亡。各种针对AD的临床试验 “淀粉样蛋白级联反应”已被证明是不成功的，这表明迫切需要重新考虑AD疾病的进展。 据报道，细胞钙（iCa 2+）和线粒体功能的改变是关键的分子贡献者 AD的发病机制。我们的实验室以前已经表明，无论是mCa 2+摄取或流出的遗传调节是一个重要因素。 在细胞应激的背景下限制线粒体功能障碍和细胞死亡的有效方法， iCa 2+。作为AD中mCa 2+交换受损的因果证据，我们产生了多个突变小鼠模型， 调节神经元NCLX表达，这是兴奋细胞中2+流出的主要机制， MCA 发现受损的线粒体钙流出会导致3xTg-1中的神经病理学和记忆力下降。 AD小鼠模型。除了改变 MCA 2+外排，我们还发现了显着的蛋白质组重塑 线粒体钙单向转运体通道（mtCU）。mtCU是急性Ca 2+摄取到脑内所必需的。 线粒体基质，调节线粒体功能。mtCU是一种多蛋白通道， 造孔、支架和调节成分。到目前为止，还没有发表的体内研究， 遗传模型，以确定mCa 2+摄取与AD疾病进展的贡献，并给出我们发表的 关于mCa 2+外流在AD发病机制中的作用的研究结果17，我们必须从机制上定义 mCa 2+摄取途径，然后进行治疗开发。在这个项目中，我们假设 mCa 2+超载是AD病理学的主要贡献者，通过促进代谢功能障碍， 神经元细胞死亡，减少mtCU依赖性mCa 2+摄取将阻止神经退行性变 和AD发病机制。此外，使用复杂的突变小鼠模型，我们将系统地定义 与AD进展和mCa 2+改变相关的线粒体代谢组学和蛋白质组学变化 通量最理想的情况是，这些研究将确定治疗AD的新治疗靶点。

SUMMARY Currently, ~5.8 million Americans suffer from Alzheimer's disease (AD)1 and there remain no approved therapeutics to lessen the associated neuronal dysfunction and cell death. Various AD clinical trials targeting the “amyloid cascade” have proven unsuccessful, suggesting a dire need to rethink AD disease progression. Alterations in cellular calcium (iCa2+) and mitochondrial function are reported as critical molecular contributors to AD pathogenesis. Our lab has previously shown that genetic modulation of either mCa2+ uptake or efflux is a powerful way to limit mitochondrial dysfunction and cell death in the context of cell stress featuring elevated iCa2+. As causal evidence of impaired mCa2+ exchange in AD, we generated multiple mutant mouse models to modulate neuronal NCLX expression, the primary mechanism for 2+ efflux in excitable cells, and mCa discovered that impaired mitochondrial calcium efflux proceeds neuropathology and memory decline in 3xTg- AD mouse model. In addition to alterations in mCa 2+ efflux, we also discovered significant proteomic remodeling of the mitochondrial calcium uniporter channel (mtCU). The mtCU is required for acute Ca2+ uptake into the mitochondrial matrix where it regulates mitochondrial function. The mtCU is a multiprotein channel, consisting of pore-forming, scaffold, and regulatory components. To date, there are no published in vivo studies using genetic models to define the contribution of mCa2+ uptake with AD disease progression and given our published findings regarding the role of mCa2+ efflux in AD pathogenesis17, it's imperative that we mechanistically define the mCa2+ uptake pathway prior to proceeding with therapeutic development. In this project, we hypothesize that mCa2+overload is a primary contributor to AD pathology by promoting metabolic dysfunction and neuronal cell death, and that reducing mtCU-dependent mCa2+ uptake will impede neurodegeneration and AD pathogenesis. Further, using complex mutant mouse models we will systematically define the mitochondrial metabolomic and proteomic changes associated with AD progression and alterations in mCa2+ flux. Optimally, these studies will identify new therapeutic targets for the treatment of AD.