项目申请人和其它科研工作者已经发现人类线粒体DNA古老变异类型（单倍型）与多种疾病的发生有关。但是，线粒体单倍型在疾病发生中的作用机制仍不明确。根据我们近期发表的工作以及部分前期研究结果，我们发现不同线粒体单倍型对疾病发生的影响不仅是因为氧化磷酸化（OXPHOS）功能变化所致的ATP生成改变和ROS对细胞的损伤作用。OXPHOS功能变化所致的核-线粒体相互作用（逆向信号通路）改变极有可能在疾病发生过程中起着重要的作用。基于这一观点，我们将以中国人线粒体单倍型为研究对象，绘制中国人线粒体单倍型的核-线粒体相互作用图谱。随后通过细胞生物学以及分子流行病学技术来明确线粒体单倍型是如何通过调节OXPHOS功能来改变核-线粒体的相互作用，并以此进一步影响疾病的发生。本课题若能完成，不仅能够进一步阐明线粒体单倍型在疾病发生中的核机制；还将为单倍型相关疾病的个性化预防和治疗提供理论支持。

It is not surprise that the mitochondrial DNA (mtDNA) haplogroup plays a role in multiple degenerative diseases such as cancer, aging and osteoarthritis. However, as most of these studies are purely descriptive, there remains a yawning gap in the understanding of the association of mtDNA haplogroup with diseases. Previously, we had showed that mtDNA haplogroups may play roles in the risk of human diseases through mitochondrial-mediated signaling pathways (retrograde signaling pathways) in addition of altered ATP generation and ROS levels. To uncover the underlying mechanism of mtDNA haplogroup in human disease, we are planning to construct 23 fusion cells of different haplogroups from the 11 major branches of phylogenetic tree in China and the oxidative phosphorylation (OXPHOS) of different haplogroups will be determined. Next, the gene expression profiles will be analyzed through RNA-sequencing to build a network of mitochondrial-nuclear interaction (retrograde signaling). At last, we will ask how OXPHOS regulate the mitochondrial-mediated retrograde signaling. We expect that our proposed research will provide important and previously unrevealed mechanisms of mtDNA haplogroup in the pathogenesis of multiple mitochondrial related degenerative diseases.