线粒体是细胞内的“能量工厂”，通过氧化磷酸化产生ATP，以提供细胞生命活动所需。我们前期与法国Prof. Jean-Paul团队合作，共同报道了第一例以肾脏受累为首发表现的线粒体细胞病，明确了8969G>A突变可阻碍质子转运、影响ATP合酶及线粒体呼吸功能，进而引发线粒体功能障碍、参与肾脏疾病发生的作用机制；并在此基础上分别构建了携带突变的杂合细胞系和酵母株。根据前期工作，我们提出假说，核基因的表观遗传调控可能只应对一定范围内的线粒体功能障碍，从而引发下游不同信号转导系统的活化。进一步拟利用已构建、不同突变异质性的杂交细胞系，筛选能量代谢相关的调控系统。同时，法国合作团队提出以酵母体系模拟线粒体疾病，利用已构建的、携带突变的酵母株建立了简单的功能评估体系，帮助筛选线粒体活性药物。在此基础上，通力合作，利用各自具备的线粒体能量代谢评估平台，以明确候选药物的作用及机制，解释线粒体功能障碍与表观遗传调控的关系。本研究正是基于前期中法两个团队在线粒体突变功能研究的合作基础上，发挥各自的技术优势，从而找寻mtDNA突变异质性、基因表达谱异质性与临床表型异质性的相关关联的枢纽靶点，并从中筛选线粒体

Mitochondria are unusual organelles, acting as the power plants of the cell and have their own genome. The mitochondrial DNA (mtDNA) codes for the most important polypeptides of the mitochondrial energy generating system OXPHOS, which generates much of cellular energy by the oxidation of dietary calories with oxygen. The teams of Jean-Paul di Rago and Huimei Chen study, since two years, the case of a Chinese female who was diagnosed at the age of 14 with a relatively common nephropathy (of the IgA type). She further developed neurological and muscle disorders, which led us to supect that the disease process had possibly a mitochondrial origin. We indeed demonstrated that the disease was caused by a mutation of the mitochondrial DNA (G8969A) and showed that this mutation impairs the process of oxidative phosphorylation, which provides the cells with most of their energy requirements under the form of ATP molecules. We now want to go further into the comprehension of the effects of this mutation on the functioning of the cell and search for therapeutic molecules. We have for this project a yeast model of the G8969A mutation and stable trans-mitochondrial cybrid cells lines derived from patient’s cells.