线粒体钙稳态异常驱动肝癌线粒体基因组突变的作用机制研究

Mitochondrial genome mutation is closely related to the tumorigenesis and tumor progression. Mitochondria DNA (mtDNA) mutation has aroused profound attention in the early-stage diagnosis and treatment in tumor, which is of extreme importance in illustrating the underlying mechanism theoretically and clinically. To date, the abnormal replication of mtDNA is regarded as the main cause promoting the generation of Mitochondrial genome mutation is closely related to the tumorigenesis and tumor progression. Mitochondria DNA (mtDNA) mutation has aroused profound attention in the early-stage diagnosis and treatment in tumor, which is of extreme importance in illustrating the underlying mechanism theoretically and clinically. To date, the abnormal replication of mtDNA is regarded as the main cause promoting the generation of mtDNA mutation, and the mitochondrial dysfunction in fission and fusion is important for the accumulation of mtDNA mutation. While the key role that regulates these two processes remains unclear. By dynamically regulating the mitochondrial homeostasis, mitochondrial calcium (Ca2+) palys a significant role in intramitochondrial enzymes activation, mitochondrial dynamics, cell survival, and has shown to be associated with tumor progression. In previous study, we found that mitochondrial Ca2+ imbalance can induce regular changes of mtDNA mutation in hepatocellular carcinoma cells (HCC). Therefore, based on our previous understanding on the mitochondria and HCC, we aim to elucidate the biological influence of mitochondrial Ca2+ homeostasis remolding in biogenesis and progression of mitochondrial genome mutation in HCC cells, thus to comprehensively explain the mechanism involved in the regulation of mitochondrial Ca2+ homeostasis remolding induced malignant transformation of HCC cells. This project will facilitate the understanding on molecular pathology of HCC and provide new potential targets for HCC diagnosis and treatment.

线粒体基因组（mtDNA）突变与肿瘤密切相关，阐明其产生及进化机制有重要的理论和临床指导价值。我们前期研究发现线粒体钙稳态异常显著影响线粒体功能，并在肿瘤恶性进展中扮演关键角色。进一步预实验发现，肝癌细胞中异常的线粒体钙水平能够驱动特征性mtDNA突变。然而，线粒体钙稳态异常在mtDNA突变产生及进化中的作用尚待系统阐明。以往文献报道mtDNA复制异常及线粒体分裂融合动态失衡对mtDNA突变产生及进化发挥重要影响。据此我们提出假说：线粒体钙稳态异常可能通过影响mtDNA复制转录进程及线粒体分裂融合动态改变，驱动mtDNA突变的特征性产生及进化，最终促进肝癌恶性进展。本项目拟在以往工作基础上，深入探索线粒体钙稳态异常通过何种分子机制调控mtDNA复制及线粒体分裂融合，进而驱动mtDNA突变产生与进化，全面认识线粒体钙稳态异常对肝癌恶性进展的影响，为肝癌防治提供新的理论基础。

线粒体基因组（mtDNA）突变与肿瘤密切相关，阐明其产生及进化机制有重要的理论和临床指导价值。我们前期研究发现线粒体钙稳态异常显著影响线粒体功能，并在肿瘤恶性进展中扮演关键角色。进一步预实验发现，肝癌细胞中异常的线粒体钙水平能够驱动特征性mtDNA突变。然而，线粒体钙稳态异常在mtDNA突变产生及进化中的作用尚待系统阐明。以往文献报道mtDNA复制异常及线粒体分裂融合动态失衡对mtDNA突变产生及进化发挥重要影响。据此我们提出假说：线粒体钙稳态异常可能通过影响mtDNA复制转录进程及线粒体分裂融合动态改变，驱动mtDNA突变的特征性产生及进化，最终促进肝癌恶性进展。本项目拟在以往工作基础上，深入探索线粒体钙稳态异常通过何种分子机制调控mtDNA复制及线粒体分裂融合，进而驱动mtDNA突变产生与进化，全面认识线粒体钙稳态异常对肝癌恶性进展的影响，为肝癌防治提供新的理论基础。