Hepatic Manifestations of Mendelian Disorders of Cholesterol Biosynthesis and Cellular Metabolism

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

10.1101/2021.04.20.440500 ◽

2021 ◽

Author(s):

Christina Iwert ◽

Julia Stein ◽

Christine Appelt ◽

Katrin Vogt ◽

Roman Josef Rainer ◽

...

Keyword(s):

T Cells ◽

Cell Differentiation ◽

T Cell ◽

Protein Expression ◽

Cd8 T Cells ◽

Effector Cell ◽

Cholesterol Biosynthesis ◽

Cellular Metabolism ◽

Mitochondrial Morphology ◽

Effector T Cell

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.

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The Effect of Oxidized Cholesterol on the Aorta of Rabbits- Scanning Electron Microscopic Observations

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100054327 ◽

1982 ◽

Vol 40 ◽

pp. 340-341

Author(s):

S. K. Pena ◽

C. B. Taylor ◽

J. Hill ◽

J. Safarik

Keyword(s):

Cholesterol Biosynthesis ◽

Cholesterol Content ◽

Arterial Injury ◽

Electron Microscopic ◽

Aortic Smooth Muscle ◽

Oxidized Cholesterol ◽

Initial Event ◽

Membrane Structure And Function ◽

Scanning Electron Microscopic ◽

And Function

Introduction: Oxidized cholesterol derivatives have been demonstrated in various cell cultures to be very potent inhibitors of 3-hvdroxy-3- methylglutaryl Coenzyme A reductase which is a principle regulator of cholesterol biosynthesis in the cell. The cholesterol content in the cells exposed to oxidized cholesterol was found to be markedly decreased. In aortic smooth muscle cells, the potency of this effect was closely related to the cytotoxicity of each derivative. Furthermore, due to the similarity of their molecular structure to that of cholesterol, these oxidized cholesterol derivatives might insert themselves into the cell membrane, alter membrane structure and function and eventually cause cell death. Arterial injury has been shown to be the initial event of atherosclerosis.

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