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Anoxia─lack of oxygen─commonly occurs during ischaemic heart disease. Using yeast, worms and mice, Hannich et al. show that anoxia-associated tissue injury and cell death are due to accumulation of a non-canonical sphingolipid, 1-deoxydihydroceramide, that damages the cytoskeleton.
Increased mitochondrial DNA (mtDNA) replication frequency is shown to lead to defects in maintenance of the nuclear genome due to reallocation of nucleotides to mitochondria, challenging the proposed direct role of mtDNA mutations as drivers of cellular and organismal ageing in mammalian progerias.
After development, adult skeletal muscle retains the capacity to regenerate by activating muscle stem cells. Here the authors demonstrate that the glycosylphosphatidylinositol-anchored membrane protein GAS1, which is induced in muscle stem cells with age, suppresses muscle regenerative capacity but can be inhibited by glial cell line-derived neurotrophic factor (GDNF).
The cellular effects of cold preservation in heart transplantation and how warm ischaemia leads to damage are unclear. Here the authors identify succinate accumulation as a major damaging metabolic change in warm ischaemia.
The liver is a heterogeneous organ organized in lobules that are radially polarized. The use of single-cell spatial transcriptomics has revealed that half of hepatic genes are differentially expressed across the lobule. Ben-Moshe et al. show how a multi-omics approach, which consists of transcriptomics, micro RNA profiling and proteomics, allows for characterization of liver heterogeneity with higher resolution.
Cancer cells increase serine synthesis; however, exogenous serine is required for maximal proliferation. Here the authors show that the demand for oxidized NAD+ constrains serine synthesis, which is needed for purine production to support cell proliferation.
Tajima and colleagues identify mitochondrial lipoylation as a post-transcriptional molecular signature of aged brown adipose tissue (BAT) in mice. Reduced mitochondrial lipoylation is tightly coupled with the age-associated decline in BAT function, whereas enhanced lipoylation restores BAT activity in aged mice.
The role of skeletal muscle in non-shivering thermogenesis is not fully elucidated. Here the authors show that, in muscle, phospholipids can influence whole-body metabolic rate and counteract obesity by altering calcium signalling and inducing energy expenditure.
Asano et al. dissect the functional difference between the soluble and membrane-bound forms of RANKL. Membrane-bound RANKL is sufficient for most physiological RANKL functions, whereas soluble RANKL promotes bone metastases by stimulating tumour cell migration to bone, without affecting tumour cell growth or osteoclast differentiation.
Chen et al. report that TGF-β signalling, although largely considered anti-inflammatory, has proinflammatory effects on endothelial cells. Inhibition of endothelial TGF-β signalling decreases atherosclerosis in mice and reverts established plaques, in part by decreasing endothelial-to-mesenchymal transitions.
Some follicular B cell lymphomas harbour activating mutations in RRAGC, activator of the nutrient sensor mTORC1. Here the authors show that these mutations confer insensitivity to nutrient deprivation and synergize with paracrine cues from the supportive T cell microenvironment to accelerate lymphomagenesis, but impose vulnerability to inhibition of mTORC1.
Folgueira et al. show that dopamine signalling in the lateral hypothalamic area and the zona incerta reduces body weight and increases energy expenditure by increasing brown adipose tissue thermogenesis in rodents. Weight loss and increased energy expenditure were also observed in patients treated with a dopamine receptor 2 agonist.
Brown adipose tissue (BAT) has high thermogenic potential and is considered a promising target to counteract obesity. Here de Jong et al. demonstrate that human BAT is more similar to classical brown than to beige adipose tissue from mice kept at thermoneutrality and challenged with a high-fat diet.
Although germline removal normally extends Caenorhabditis elegans lifespan, Lee et al. show that low temperature does not extend lifespan in germline-lacking mutant worms. Cold temperatures (10 °C, 15 °C) delay germline stem cell exhaustion, releasing prostaglandin E2 hormone, which induces cbs-1 in the intestine to produce hydrogen sulfide and prolong lifespan.
m6A mRNA methylation regulates several cellular processes, including cancer progression and stem cell maintenance. Here, De Jesus and colleagues demonstrate that the m6A landscape segregates human type 2 diabetic islets from controls and that m6A is fundamental for human β-cell biology.
Macrophages engage in a sequence of dynamic functional changes during immune responses. Here the authors elucidate a two-stage remodelling of the tricarboxylic acid cycle during this process, which is driven by regulation of the pyruvate dehydrogenase and the oxoglutarate dehydrogenase complexes, and causes transient accumulation of immunoregulatory metabolites.
Spontaneous control of HIV is linked to the ability of CD8+ T cells to eliminate infected CD4+ T cells. Here, the authors uncover metabolic differences between HIV-specific, central memory CD8+ T cells from spontaneous HIV controllers and antiretrovirally treated non-controllers, and show that in vitro metabolic reprogramming enhances the antiviral response in non-controllers cells.
Increased metabolic activity promotes HIV-1 infection in CD4 T lymphocytes, but the contribution of different metabolic pathways is unclear. Here the authors show that carbon entry into the citric acid cycle is required to support the early stages of HIV-1 infection.