Mitochondrial Targets in Methylmalonic Acidemia

甲基丙二酸血症是一种遗传性代谢紊乱，影响1：48,000名新生儿，导致神经损伤和全身性脑组织损伤，迄今很少或没有有效的治疗方法。甲基丙二酸(MMA)的蓄积被认为导致部分线粒体电子传递链抑制，导致能量缺乏和酸中毒，类似于缺血/再灌注时发生的情况。这一应用是基于这样一种假设，即线粒体靶向药物可以有效地防止甲基丙二酸血症中的组织损伤，这些药物可以防止能量剥夺或缺血/再灌注导致的细胞死亡。本应用的具体目的是：1.确定MMA对线粒体功能的影响。2.探讨线粒体膜通透性转变在甲基丙烯酸甲酯(MMA)诱导的线粒体改变中的作用。3.探讨三磷酸腺苷敏感性钾通道在甲基丙烯酸甲酯引起的线粒体损伤中的作用。4.研究甲基丙烯酸甲酯对神经细胞活性及脑组织结构和功能的影响。这些研究将涉及使用体外模型，包括大鼠脑线粒体、细胞培养和暴露于甲基丙烯酸甲酯的大鼠脑片。研究人员还将使用体内大鼠模型，包括全身和脑内注射MMA。将在所有使用的模型中评估ATP敏感性K+通道激动剂(如二氮卓)和通透性转换抑制剂(如环孢素A)可能的保护作用。这项研究的结果将有助于了解甲基丙二酸学术界组织损伤的机制，并有可能确定线粒体在该疾病中的组织保护靶点。

Methylmalonic acidemia is an inherited metabolic disorder that affects 1:48,000 newborns and leads to neurological impairment and generalized brain tissue damage, with little or no effective treatment to date. Accumulated methylmalonate (MMA) is believed to cause partial mitochondrial electron transport chain inhibition, resulting in energetic deprivation and acidosis similar to those occurring in ischemia/reperfusion. This application is based on the hypothesis that mitochondrially-targeted drugs that protect against cell death induced by energy deprivation or ischemia/reperfusion could prove effective in preventing tissue damage in methylmalonic acidemia. The specific aims of this application are: 1. to determine the effects of MMA on mitochondrial function. 2. To evaluate the role of the permeability transition, a non-selective inner mitochondrial membrane permeabilization caused by excessive Ca2+ uptake, in mitochondrial alterations induced by MMA. 3. To assess the role of ATP-sensitive K+ channels in mitochondrial alterations induced by MMA. 4. To study the effects of mitochondrial alterations promoted by MMA and their prevention on neural cell viability and brain structure and function. These studies will involve the use of in vitro models including rat brain mitochondria, cell cultures, and rat brain slices exposed to MMA. The investigators will also use in vivo rat models involving systemic and intracerebral injections of MMA. The possible protective effects of ATP-sensitive K+ channel agonists (such as diazoxide) and permeability transition inhibitors (such as cyclosporin A) will be evaluated in all models used. Results obtained in this study will contribute toward the understanding of mechanisms of tissue damage in methylmalonic academia, and potentially determine mitochondrial targets for tissue protection in this disease.