D型2-羟基戊二酸(D-2HG)作为一种致癌代谢物，可通过竞争性抑制α-酮戊二酸依赖的双加氧酶活性而影响多种细胞生理过程。然而，D-2HG影响线粒体形态结构的分子机制尚未有报道。本研究通过对秀丽隐杆线虫进行EMS诱变筛选，发现编码D型2-羟基戊二酸脱氢酶基因(hgdh-1)突变可导致线粒体呈现不规则增大的表型，这与线虫丙酸β氧化代谢缺陷突变体线粒体的异常形态相似，推测二者在遗传学上可能作用于同一遗传通路。此外，补充维生素B12或饲喂K12型大肠杆菌可显著改善上述突变体线粒体的形态和功能异常。综合上述实验结果，本项目旨在研究线虫hgdh-1突变体中D-2HG的累积影响丙酸β氧化代谢通路和线粒体稳态平衡的分子机制，以及食物或肠道菌群与宿主的相互作用调控线粒体稳态平衡的作用机理，以期为解析一型D型2-羟基戊二酸尿症、丙酸代谢缺陷或相关肿瘤的致病机理和治疗提供一定的理论依据。

D-2HG acting as an oncometabolite affects a variety of cellular physiological processes by inhibiting α-KG-dependent dioxygenases. However, mitochondrial homeostasis caused by high D-2HG levels remains incompletely understood. Here, hgdh-1 gene involved in the clearance of D-2HG was analyzed by EMS screen and mutant mapping, sequencing, and characterization, whose mutations caused the similarly abnormally enlarged mitochondrial morphology with propionate shunt mutants. We speculated that these genes may function together in a genetic pathway, and a novel link will be studied between propionate metabolism and oncometabolite (D-2HG) production. The mitochondrial dysfunctions of hgdh-1 and propionate shunt mutants are relieved by supplementing of vitamin B12 or feeding with E. coli K12 strains. Based on these results, this project aims to study the effect of D-2HG accumulation caused by hgdh-1 mutations on propionate shunt pathway and mitochondrial dysfunction, and the interaction between host and microbiota on metabolic flexibility of inborn propionate metabolic defects, which may clarify the mechanistic and provide the therapeutic insights for understanding and treating D-2-hydroxyglutaric aciduria type I, propionate metabolic defect disease and associated tumors.