线粒体动力学改变在MELAS发病机制中的作用研究

Mitochondiral encephalomyopathy with lactic acidemia and stroke-like episodes (MELAS) is a common mitochondrial disease with high lethal and disability caused by mitochondrial DNA(mtDNA) mutations. The load of mutated mtDNA in cells plays key role in pathogenesis of disease. The appearance of numerous long strip and spheroid mitochondria in the muscle fibers indicated abnormal mitochondrial fission and fusion, i.e, dynamic dysfunction which cause decrease of clearance of abnormal mitochondria. Correction of the abnormal mitochondrial dynamics may stop the development of MELAS. However, it is still not clear about the regulation and pattern of mitochondrial dynamics as well as mitophagy in the disease. Based on our findings in previous work, we will determine the effects of mutant mtDNA load on mitochondrial dynamics and mitophagy in the muscle fibers by: 1)electron microscopy and immunoelectron microscopy examination to observe the ultrastructural changes of mitochondrial dynamics and mitophagy in patients with various mutant load of mtDNA, 2) observing the location of mitochondrial fusion, fission and mitophagy related proteins in different abnormal mitochondria,3) Using western blot and RT PCR to study the expression of mitochondrial fusion, fission, mitophagy related proteins.The results of this study could provide new evidence for MELAS therapy.

线粒体脑肌病伴乳酸血症和卒中样发作（MELAS）是一种线粒体基因（mtDNA）突变导致的高致残和高致死性疾病。细胞含mtDNA突变量是决定患者发病的重要因素，该病肌纤维出现大量长条状和球状线粒体提示存在线粒体分裂融合的动力学改变，导致细胞清除异常线粒体的功能下降。恢复正常线粒体动力学有望阻止疾病发展。但该病线粒体动力学存在哪些改变规律还不清楚。本课题基于前期工作，对不同mtDNA突变量MELAS患者的肌纤维进行常规和免疫电镜检查，观察线粒体分裂、融合及自噬相关蛋白在异常形态线粒体的分布；Western blot和RT-PCR方法研究骨骼肌线粒体分裂融合蛋白、线粒体自噬蛋白表达，确定不同mtDNA突变量对线粒体动力学及自噬的影响。为探讨新的MELAS治疗提供理论依据。

线粒体脑肌病伴乳酸血症和卒中样发作（MELAS）是一种线粒体基因（mtDNA）突变导致的高致残和高致死性疾病。本研究围绕线粒体自噬障碍展开研究。研究结果显示MELAS患者的骨骼肌细胞中存在大量长条状和球状线粒体，而自噬小体非常少见；Western blot检测也发现骨骼肌和成纤维细胞的自噬相关蛋白表达不足；但是线粒体膜电位探针TMRM观察MELAS患者皮肤成纤维细胞可以发现，较正常对照组，MELAS患者组细胞内线粒体膜电位明显降低，且线粒体呈碎片化改变，上述研究结果提示在MELAS中存在线粒体自噬流障碍。后续研究将给予干预线粒体自噬的相关分子和药物，观察其清除异常线粒体的作用，为探讨新的MELAS治疗提供理论依据。

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