Volume 3 Issue 5, May 2021

Reactive oxygen species (ROS) were long considered unwanted and dangerous by-products of mitochondrial metabolism, specifically oxidative phosphorylation. More recently, evidence has indicated that mitochondrial ROS are also essential signalling molecules that unexpectedly promote longevity, through a mechanism termed mitohormesis. In this issue, Timblin et al. expand this concept to immunity, specifically macrophage function, by demonstrating that mitochondrial ROS are required to prevent an excessive immune response.

Cancer is a complex disease without a specific single origin. Despite recent advances in this field, knowledge of the relationship between the metabolic networks of tumoural cells and the normal cells from their tissue of origin is limited. Here, Mahendralingam et al., by using a combination of multi-omic and cell-based techniques to characterize the metabolic programs of normal mammary epithelial cells, find that mammary cancer cells preserve the metabolic network and vulnerabilities of their cells of origin, thus uncovering a new putative Achilles’ heel in breast cancer.

Endothelial cell migration is indispensable for (tumour) angiogenesis and is fuelled by glycolysis. The metabolic underpinnings have been only partially unravelled to date, partly because of the lack of appropriate tools to analyse metabolic flux at the single-cell level. In this issue, Wu et al. introduce a novel imaging assay to capture glycolytic flux during motion in single endothelial cells. With this new tool, the authors uncovered a glycolysis-driven cytoskeletal remodelling apparatus that propels endothelial cell motility.

Bile acids are shown to enter the brain and regulate short-term reductions in food intake after a meal by inhibiting neuropeptide release from agouti-related peptide/neuropeptide Y neurons.

UCP1 is exclusively expressed in brown and beige adipocytes, where it drives thermogenesis through futile substrate cycling. Mills et al. identify a endocrine pathway mediated by the UCP1 catabolic circuit that antagonizes liver inflammation by lowering the concentration of succinate in the liver extracellular fluid.

Timblin et al. demonstrate that LPS or hydroxyoestrogen-induced mitochondrial stress triggers mitohormesis in macrophages, restraining inflammatory gene activation by suppressing oxidative metabolism.

Sprenger et al. find that cytosolic pyrimidine levels regulate the release of mitochondrial DNA and activation of cGAS–STING.

Using a CRISPR genetic screen for solute transporters and a metabolic compound library screen, Li et al. identify purine transport and de novo synthesis as key regulators of BRD4, a histone acetylation reader.

Cancer metabolism adapts the metabolic network of its cell of origin. Mahendralingam et al. find that lineage-rooted metabolic identities of normal mammary cells reflect breast cancer subtype metabolism.

A high-throughput chemical screen identifies the salt-inducible kinase inhibitor HG-9-91-01 as a driver of β cell proliferation, acting through an ATF6-dependent unfolded protein response.

Irx3 and Irx5 are effectors of the FTO locus, which is associated with obesity. Son et al. show regulation of hypothalamic neurogenesis by Irx3 and Irx5, uncovering a role for these genes in leptin response and energy homeostasis.

Wu, Harrison and colleagues visualize lactate production at subcellular resolution in migrating endothelial cells and identify hotspots of glycolytic activity, mediated by RhoA and the glucose transporter SLC2A3, that couple cellular energy metabolism with cytoskeleton remodelling and cell motility.