The mitochondrial DNAJC co-chaperone TCAIM reduces α-ketoglutarate dehydrogenase protein levels to regulate metabolism
Jiahui Wang, Xiang Yu, Zhong Youhuan, Xiaomin Ma, Yuanzhu Gao, Zhou Dejian, Wang Jie, Yinkun Fu, Fan Shi, Su Juncheng, Masha Huang, Haigis Marcia, Wang Peiyi, Yingjie Xu, Yang Wen
Abstract
Mitochondrial heat shock proteins and co-chaperones play crucial roles in maintaining proteostasis by regulating unfolded proteins, usually without specific target preferences. In this study, we identify a DNAJC-type co-chaperone: T cell activation inhibitor, mitochondria (TCAIM), and demonstrate its specific binding to α-ketoglutarate dehydrogenase (OGDH), a key rate-limiting enzyme in mitochondrial metabolism. This interaction suppresses OGDH function and subsequently reduces carbohydrate catabolism in both cultured cells and murine models. Using cryoelectron microscopy (cryo-EM), we resolve the human OGDH-TCAIM complex and reveal that TCAIM binds to OGDH without altering its apo structure. Most importantly, we discover that TCAIM facilitates the reduction of functional OGDH through its interaction, which depends on HSPA9 and LONP1. Our findings unveil a role of the mitochondrial proteostasis system in regulating a critical metabolic enzyme and introduce a previously unrecognized post-translational regulatory mechanism.