Targeted degradation of the α-ketoglutarate dehydrogenase mediated by a mitochondrial DNAJC protein regulates metabolism

ABSTRACT:

Mitochondrial heat shock proteins and co-chaperones play essential roles in maintaining proteostasis. They are renowned for regulating unfolded proteins, usually without specific target preferences. In this study, we identified T cell activation inhibitor, mitochondria (TCAIM), as a novel DNAJC-type co-chaperone and demonstrated its specific binding to α-ketoglutarate dehydrogenase (OGDH), a key rate-limiting enzyme of mitochondrial metabolism. Unexpectedly, this interaction leads to the suppression of OGDH function and subsequent carbohydrate catabolism in both cultured cells and murine models. We further revealed that TCAIM binds to OGDH without inducing changes in its apo structure through cryo-EM resolution of the human TCAIM-OGDH complex. Most significantly, we discovered that TCAIM facilitates the degradation of functional OGDH through this binding, in a manner dependent on mitochondrial heat shock proteins and proteases. Hence, our study unveils an unprecedented role of the mitochondrial proteostasis system in the targeted degradation of a crucial metabolic enzyme. It also introduces a novel post-translational regulatory mechanism.

INSTRUMENT(S): Liquid Chromatography MS - negative - reverse phase, Liquid Chromatography MS - positive - reverse phase

PROVIDER: MTBLS10440 | MetaboLights | 2024-12-03

REPOSITORIES: MetaboLights