bims-mimeim 2021-03-07 papers

Issue of 2021–03–07
three papers selected by
Matthew C. Sinton, University of Glasgow

Metabolites. 2021 Feb 22. pii: 124. [Epub ahead of print]11(2):

Mitochondrial Lipid Signaling and Adaptive Thermogenesis.

Helaina Von Bank, Mae Hurtado-Thiele, Nanami Oshimura, Judith Simcox.

Thermogenesis is an energy demanding process by which endotherms produce heat to maintain their body temperature in response to cold exposure. Mitochondria in the brown and beige adipocytes play a key role in thermogenesis, as the site for uncoupling protein 1 (UCP1), which allows for the diffusion of protons through the mitochondrial inner membrane to produce heat. To support this energy demanding process, the mitochondria in brown and beige adipocytes increase oxidation of glucose, amino acids, and lipids. This review article explores the various mitochondria-produced and processed lipids that regulate thermogenesis including cardiolipins, free fatty acids, and acylcarnitines. These lipids play a number of roles in thermogenic adipose tissue including structural support of UCP1, transcriptional regulation, fuel source, and activation of cell signaling cascades.

Keywords: acylcarnitine; brown adipose tissue; cardiolipin; free fatty acid; glycerolipids; ketone; lipids; mitochondria; plasmalogen; thermogenesis

DOI: https://doi.org/10.3390/metabo11020124

Nat Commun. 2021 Mar 05. 12(1): 1460

Mitochondrial arginase-2 is essential for IL-10 metabolic reprogramming of inflammatory macrophages.

Mitochondria are important regulators of macrophage polarisation. Here, we show that arginase-2 (Arg2) is a microRNA-155 (miR-155) and interleukin-10 (IL-10) regulated protein localized at the mitochondria in inflammatory macrophages, and is critical for IL-10-induced modulation of mitochondrial dynamics and oxidative respiration. Mechanistically, the catalytic activity and presence of Arg2 at the mitochondria is crucial for oxidative phosphorylation. We further show that Arg2 mediates this process by increasing the activity of complex II (succinate dehydrogenase). Moreover, Arg2 is essential for IL-10-mediated downregulation of the inflammatory mediators succinate, hypoxia inducible factor 1α (HIF-1α) and IL-1β in vitro. Accordingly, HIF-1α and IL-1β are highly expressed in an LPS-induced in vivo model of acute inflammation using Arg2-/- mice. These findings shed light on a new arm of IL-10-mediated metabolic regulation, working to resolve the inflammatory status of the cell.

DOI: https://doi.org/10.1038/s41467-021-21617-2

Elife. 2021 Mar 01. pii: e63326. [Epub ahead of print]10

The mTORC1-mediated activation of ATF4 promotes protein and glutathione synthesis downstream of growth signals.

Margaret E Torrence, Michael R MacArthur, Aaron M Hosios, Alexander J Valvezan, John M Asara, James R Mitchell, Brendan D Manning.

The mechanistic target of rapamycin complex 1 (mTORC1) stimulates a coordinated anabolic program in response to growth-promoting signals. Paradoxically, recent studies indicate that mTORC1 can activate the transcription factor ATF4 through mechanisms distinct from its canonical induction by the integrated stress response (ISR). However, its broader roles as a downstream target of mTORC1 are unknown. Therefore, we directly compared ATF4-dependent transcriptional changes induced upon insulin-stimulated mTORC1 signaling to those activated by the ISR. In multiple mouse embryo fibroblast (MEF) and human cancer cell lines, the mTORC1-ATF4 pathway stimulated expression of only a subset of the ATF4 target genes induced by the ISR, including genes involved in amino acid uptake, synthesis, and tRNA charging. We demonstrate that ATF4 is a metabolic effector of mTORC1 involved in both its established role in promoting protein synthesis and in a previously unappreciated function for mTORC1 in stimulating cellular cystine uptake and glutathione synthesis.

Keywords: cancer biology; cell biology; human; mouse; rat

DOI: https://doi.org/10.7554/eLife.63326