线粒体分裂抑制肿瘤细胞“线粒体-内质网相互作用膜结构”形成的作用及功能研究

Mitochondrial-ER interactive membrane (MEIM), the junction between the mitochondrial outer membrane and the endoplasmic reticulum membrane, plays important roles in a variety of biological functions. However, how the formation of MEIM is regulated and whether it plays a key role in the progression of malignant tumors has not been elucidated. Our previous studies have found that the length of MEIM in hepatocellular carcinoma (HCC), colorectal cancer and breast cancer tissues was significantly decreased and was positively correlated with mitochondrial length. Additionally, we have also demonstrated that mitochondrial fission was significantly enhanced in HCC tissues and promoted the progression of HCC (Autophagy 2016 IF: 9.11). Furthermore, the enhancement of mitochondrial fission in HCC cell significantly inhibited the co-localization of mitochondria and ER. Taken together, these results suggested that mitochondrial fission is most likely to inhibit the formation of MEIM in tumor cells. Therefore, we aim to explore the role of mitochondrial fission in the regulation of MEIM. Furthermore, the underling mechanism will also be explored. Therefore, this project will facilitate our understanding on the molecular pathology of tumor and provide new potential targets for tumor treatment.

线粒体-内质网相互作用膜结构（MEIM）是线粒体膜与内质网膜形成的紧密物理连接，在多种细胞功能中发挥关键作用。新近研究表明MEIM异常与神经疾病、糖尿病发病相关。然而肿瘤细胞MEIM形成是否异常，如何被调控，在肿瘤中是否发挥关键作用尚未阐明。我们电镜观察发现：多种癌组织MEIM长度显著缩短，并与线粒体分裂水平负相关。另外我们已证实肝癌细胞线粒体分裂增强，并显著促进肝癌进展（Autophagy.2016.IF:9.11）。进一步还发现增强线粒体分裂可显著抑制线粒体与内质网共定位。以上结果提示肿瘤细胞线粒体分裂抑制MEIM形成。因此，本项目拟从MEIM的崭新视角，利用已构建的线粒体分裂及MEIM肿瘤细胞模型和丰富的临床样本，系统研究线粒体分裂对MEIM的调控作用及潜在机制，进而探讨MEIM异常影响肿瘤生长的功能意义。本项目的开展不但可进一步加深对肿瘤病理机制的理解，也可为肿瘤治疗提供新思路。

线粒体-内质网相互作用膜结构（MAM）是线粒体膜与内质网膜形成的紧密物理连接，在多种细胞功能中发挥关键作用。然而肿瘤细胞MAM形成是否异常，如何被调控，在肿瘤中是否发挥关键作用尚未系统阐明。我们通过电镜定量观察发现：多种癌组织MAM长度显著缩短，并与线粒体分裂水平负相关。另外我们已证实肝癌细胞线粒体分裂增强，并显著促进肝癌进展。进一步还发现增强线粒体分裂可显著抑制线粒体与内质网共定位。进而，本项目从MAM的崭新视角，利用已构建的线粒体分裂及MAM肿瘤细胞模型和丰富的临床样本，系统研究线粒体分裂对MAM的调控作用及潜在机制，通过研究发现：在HCC病人组织和小鼠肝癌模型中线粒体-内质网结构偶联长度、数量都显著降低；HCC细胞中乳酸可以诱导线粒体分裂并抑制MAM结构形成；解离的MAM结构通过抑制线粒体钙转运，抑制线粒体氧化呼吸水平的作用。本项目的开展可进一步加深对肿瘤病理机制的理解，也可为肝癌治疗提供新思路。