A Novel DNAJ Protein, TCAIM, Drives Proteolysis of Α-Ketoglutarate Dehydrogenase and Regulates Mitochondrial Metabolism.

Mitochondria play essential roles in metabolism, and the proteostasis system is important for almost all biological processes that occur in this double-membrane-enclosed organelle, including metabolic functions. In this study, we identified a novel mtHSP70 co-chaperone DNAJC protein, TCAIM, that specifically binds to the E1 subunit of α-ketoglutarate dehydrogenase (OGDH). Using the single-particle cryo-EM technique, we determined the binding structures of TCAIM and OGDH. We further demonstrated that by binding to the native form of OGDH, TCAIM specifically mediates the degradation of OGDH and regulates its activity in vivo in a mtHSP70- and LONP1-dependent manner. Moreover, the lack of TCAIM changes metabolism in mice and primary cells, whereas overexpression of TCAIM decreases mitochondrial bioenergetics. Thus, this study revealed a novel mechanism by which mitochondrial metabolism could be regulated by selective degradation of an important metabolic enzyme, mediated by a DNAJC protein.