News & Views

Bone resorption by osteoclasts requires tight control, as overactivation reduces bone mass and strength. Stegen et al. demonstrate that α-ketoglutarate produced during serine synthesis promotes osteoclast development via metabolic–epigenetic coupling and could be a therapeutic target.

In nature, organisms constantly face a variety of stresses in the environment. An organism’s ability to resolve a stressful state is crucial in maintaining homeostasis. In this issue of Nature Metabolism, Wei et al. report that redox-dependent caspase cleavage of fatty acid synthase triggers a global cue for stress resolution in Caenorhabditis elegans.

A study in Nature Metabolism shows that the thyroid gland contains two subtypes of thyrocytes (the cells that produce thyroid hormones) and reveals a role for Notch signalling in regulating thyrocyte homeostasis and activity, as reduced Notch activity results in hypothyroidism.

The gene-editing tool mitoARCUS has been precisely fine-tuned to reduce m.3243A>G mitochondrial DNA (mtDNA) without harming wild-type mtDNA or nuclear DNA in vitro and in vivo, which paves the road to the first human trials.

Stress is an important risk factor for neuropsychiatric disorders such as major depression, but the underlying biological mechanisms remain largely unclear. A recent study has revealed a mechanism that regulates neuronal metabolism and mitochondrial function, and thereby drives stress susceptibility and disease outcomes.

By analysing the effect of disrupting microbiota during in vivo reprogramming, Kovatcheva et al. demonstrated that vitamin B₁₂-dependent metabolism is a limiting factor for cellular reprogramming and plasticity, and propose its therapeutic supplementation for the improvement of tissue repair.

Neuronal energization and memory formation in the fruit fly are found to be conditioned by the shuttling of alanine between glial cells and neurons. This observation highlights the emerging role of energy metabolism as a driver of tissue function.

Glucose transporter-mediated uptake of glucose is a key metabolic checkpoint in T cells. Fu et al. have identified GLUT2 as a critical regulator of CD8⁺ T cell metabolism and function in response to glucose and oxygen availability.

Group 3 innate lymphoid cells (ILC3s) maintain intestinal barrier integrity and nutrient absorption via IL-22; however, little is known about how these immune cells fuel effector function. Wu et al. now report that uptake of dietary proline acts as a critical metabolic modulator of the ILC3 transcriptome and cytokine production to maintain gut health.

Mitochondrial proteins are frequently acetylated, but most of these modifications are thought to occur non-enzymatically, rather than requiring an acetyltransferase. A new study by Akhtar and colleagues challenges this view by demonstrating that MOF, a well-characterized histone acetyltransferase, bolsters mitochondrial metabolism by acetylating the complex IV assembly factor COX17.

Brown adipose tissue has a crucial role in regulating body temperature in mammals. Recent research delves into the notion of thermogenic memory and identifies a subset of adipocytes that enhance the response to repeated stimulation events via de novo lipogenesis.

As most studies on the action of insulin in the brain have focused on men, metabolic changes during the menstrual cycle in women remain poorly understood. Using intranasal insulin administration during hyperinsulinaemic–euglycaemic clamps and functional MRI, Hummel et al. show reduced insulin sensitivity during the luteal phase.

Sa et al. identified a distinct neuronal subpopulation that controls brown adipose tissue thermogenesis. In mice fed a high-fat diet, hypothalamic GABRA5 neurons are deactivated by GABA released by surrounding astrocytes and inhibition of GABA synthesis ameliorates diet-induced obesity.

Okreglak et al. explore the molecular mechanisms that link organellar pH dynamics with the cell cycle, and find that vacuolar pH oscillates during cell cycle phases to ensure an adequate supply of amino acids during cell division. This study offers metabolic insight into the fundamental mechanisms that couple amino acid availability to the cell cycle through pH fluctuations.

In this issue of Nature Metabolism, a study shows that glutarate increases memory T cells as well as T cell cytotoxicity and reduces tumour growth. During T cell activation, glutarate levels and glutarylation increase. Glutarate inhibits α-ketoglutarate-dependent dioxygenases, and glutarylation reduces pyruvate dehydrogenase complex activity and enhances glycolysis.

The relationship between stress and gastrointestinal function is poorly understood and of major clinical importance as a potential contributor to irritable bowel syndrome, functional dyspepsia and numerous other disorders of gut–brain interaction. A recent study investigates a descending neural circuit that regulates gastric motility and is inversely modulated by chronic versus acute stress.

By combining multimodal metabolomics technologies to investigate colorectal tissues and tumours in situ, Vande Voorde et al. found tumour genotype-specific metabolic profiles and revealed the methionine-cycle enzyme AHCY to be a potential therapeutic target in colorectal cancer.

Methionine restriction modulates tumour growth and ageing processes through its influence on diverse metabolic processes. Ji et al. demonstrate that methionine restriction compromises production of hydrogen sulfide (H₂S), which impairs H₂S-mediated immune signalling and results in increased cancer progression in immunocompetent mice.

Astrocytes are usually viewed as archetypical glycolytic cells. A study now shows that fatty acid oxidation in astrocytes rearranges the respiratory chain to a configuration that safeguards neuronal functionality and proper cognitive performance in mice.

Mao et al. discover that heart failure-associated metabolic derangement results in cardiomyocyte cholesterol overload and accumulation of bile acid intermediates, which in turn trigger mitochondrial damage and inflammatory activation and thus promote heart failure.