
 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.

/pdf/a-novel-dnaj-protein-tcaim-drives-proteolysis-of-a-1giw17qm.pdf

A novel DNAJ protein, TCAIM, drives proteolysis of α-ketoglutarate dehydrogenase and regulates mitochondrial metabolism.

T cells need to adapt their cellular metabolism for effector cell differentiation. This relies on alterations in mitochondrial physiology. Which signals and molecules regulate those alterations remains unclear. We recently reported, that the mitochondrial protein TCAIM inhibits activation-induced changes in mitochondrial morphology and function and thus, CD4+ effector T cell formation. Using conditional TCAIM knock-in (KI) and knockout (KO) mice, we now show that it also applies to CD8+ T cells and more importantly, delineate the molecular processes in mitochondria by which TCAIM controls effector cell differentiation. TCAIM KI resulted in reduced activation-induced HIF1α protein expression. Metabolomics and transcriptional data in combination with mathematical flux modeling revealed an impaired induction of anabolic pathways, especially of the mevalonate pathway and cholesterol biosynthesis in TCAIM KI CD8+ T cells. Addition of cholesterol completely rescued HIF1α protein expression, activation and proliferation of TCAIM KI CD8+ T cells. At the molecular level, TCAIM delayed activation-induced mitochondria-ER contact (MERC) formation by binding to MERC promoting proteins such as RMD3 and VDAC2. In summary, we demonstrate that TCAIM suppresses effector cell differentiation by inhibiting MERC formation, which induce HIF1α-mediated increase in cellular metabolism and cholesterol biosynthesis.

https://biorxiv.org/content/10.1101/2021.04.20.440500v1.full.pdf

TCAIM controls effector T cell generation by preventing Mitochondria-Endoplasmic Reticulum Contact Site-initiated Cholesterol Biosynthesis

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TCAIM controls effector T cell generation by preventing Mitochondria-Endoplasmic Reticulum Contact Site-initiated Cholesterol Biosynthesis