线粒体功能损害在多种酰基辅酶A脱氢缺陷病发生发展过程中的作用及其应对策略

Multiple acyl-CoA dehydrogenase deficiency (MADD) is an autosomal recessive fatty acid metabolism disorder. A considerable number of late onset MADD cases have been reported to be dramatically responsive to high dosage riboflavin supplementation. Such patients are referred to as riboflavin-responsive MADD (RR-MADD). However, there is still no sufficient treatment for NRR-MADD. Mitochondrial dysfunction in MADD has been proved before. In RR-MADD, CoQ10 rather that riboflavin could correct this kind of dysfunction. So far, the conclusion about mitochondrial dysfunction and benefits from CoQ10 supplement are variable between populations. Since the function of mitochondria is dynamic, it is important to investigate it dynamically. In this research, using the MADD mouse model and fiber blast cells from MADD patients, we would test the function of mitochondria in different stages of the disease, and investigate the treatment for mitochondrial dysfunctions in each stage. Besides, by using proteomics analysis, we would try to find the key factors for mitochondrial function modification. By comparing the key factors in RR-MADD and NRR-MADD, we hope to find methods to improve the life quality for NRR-MADD patients.

多种酰基辅酶A脱氢缺陷(MADD)是一种在中国人群中相对高发的涉及线粒体脂肪酸代谢异常的遗传病,其中核黄素反应性MADD(RR-MADD)对核黄素治疗具有良好反应,而非核黄素反应性RR-MADD(NRR-MADD)目前仍没有针对性治疗手段。前期研究已证实,MADD存在线粒体功能异常,RR-MADD患者应用核黄素治疗后线粒体功能异常仍存在,应用CoQ10后这种异常可被纠正。但目前对MADD线粒体功能损伤模式、CoQ10治疗等的研究结果缺乏一致性。本研究将以前期构建的RR-MADD小鼠及患者成纤维细胞为模型，利用线粒体酶活性检测、呼吸链功能检测、蛋白质组学等方法，在体动态观察疾病不同阶段线粒体功能变化；探索线粒体损伤对于RR-MADD转归及长期预后的影响，寻求其干预措施；并寻找RR-MADD调控线粒体功能的关键靶点，通过与NRR-MADD相比较，探求改善NRR-MADD症状的治疗新策略。