Volume 5 Issue 3, March 2023

Both cell cycle arrest and secretions of senescent cells are subject to metabolic control. In this issue of Nature Metabolism, Roh et al. show that lysosomal partitioning of cholesterol potentiates inflammatory secretion during senescence.

Defective nicotinamide adenine dinucleotide (NAD⁺) metabolism is involved in various diseases. A study in Nature Metabolism identifies the cytosolic mitochondrial-RNA sensing system as a mediator that links NAD⁺ deficiency to kidney disease in humans and mice.

The rate of glycolysis increases markedly during the phagocytosis of apoptotic cells and upon macrophage activation by inflammatory stimuli. However, the motive for burning glucose differs in both conditions.

Although astrocytes are largely glycolytic, they catabolize a variety of substrates via oxidative phosphorylation in the mitochondria. In this issue, Mi et al. show that oxidative phosphorylation in astrocytes protects the brain from inflammation and degeneration by degrading excess fatty acids.

Animals need to be able to evaluate environmental pH. Mechanisms that mediate sour taste and acid sensing have been reported across species, but less is known about the detection of high pH. Mi et al. identify the gene alkaliphile, which encodes a high-pH-gated chloride channel in the gustatory system of flies.

By measuring protein abundance in blood using high-throughput antibody-based techniques, a genetic map of blood proteins in humans replicates findings from much larger studies, uncovers hundreds of new signals and bridges genetic variation to multiple diseases.

PCYT2 is an enzyme involved in lipid biosynthesis, and its genetic deficiency in zebrafish, mice and humans causes progressive muscle weakness. Importantly, PCYT2 activity declines in ageing muscles of mice and humans, and PCYT2 gene therapy in aged mice improves muscle strength, suggesting new therapeutic avenues to explore for maintaining muscle health in ageing.

Matsumura, Wei and Sakai discuss epitranscriptomic modifications and their links to metabolic disease, how genetic and environmental factors influence epitranscriptomics, and how the epitranscriptome is linked to the epigenome.

Primary cilia are shown to adjust length in response to cellular nutrient availability, with a special role for glutamine-mediated anaplerosis via the enzyme ASNS, which was found to be located at the base of cilia. Consistently, cells lacking cilia show an altered response to glutamine during metabolic stress.

Senescenct cells are shown to accumulate cholesterol in lysosomes, which upregulates mTORC1 signaling, thereby supporting the senescence-associated secretory phenotype and promoting senescence-associated inflammation.

Doke et al. show that NMN and NR supplementation has protective effects on kidney injury by preventing cisplatin-induced release of cytosolic mitochondrial RNA and subsequent activation of the RIG-I pathway and inflammation.

Schilperoort et al. explore the mechanisms underlying dynamic changes in macrophage metabolism that support efferocytosis. They show that transient glycolysis and subsequent lactate production are necessary to execute continual efferocytosis, as opposed to prolonged glycolysis observed in pro-inflammatory macrophages.

Mi, Qi et al. identify a mechanism through which defective oxidative phosphorylation in astrocytes deregulates astroglial lipid homeostasis and subsequently impacts neurons and microglial cells, thus triggering neuronal damage and microglial reactivity.

The authors identify a high-pH-activated chloride channel as a taste receptor responsible for the avoidance of alkaline foods in fruit flies, laying the groundwork for future research on alkaline taste sensation in other animals.

Sympathetic innervation of brown and white adipose tissue is shown to be promoted by zinc released from thermogenic adipocytes, revealing a positive feedback mechanism for regulation of thermogenesis and thereby energy expenditure.

Human mutations in PCYT2 result in severe pathology with failure to thrive and progressive degenerative disease. Cikes et al. demonstrate that loss of PCYT2-synthesized phosphatidylethanolamines in muscle impairs sarcolemmal lipid bilayer stability and mitochondrial homeostasis, leading to muscle degeneration and premature ageing in mice.

Koprulu et al. integrate antibody-based proteomic data with genomics to link protein-encoding genes to human metabolic disease.