Articles in 2023

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.

Mosteiro et al. show that inhibition of Notch, a signaling pathway frequently associated with cell-fate decisions during development, impairs thyrocyte homeostasis in an active subset of thyrocytes in adult mice through mitochondrial dysfunction and decreased ROS, thereby causing hypothyroidism.

Macrophages that clear apoptotic cells (efferocytosis) proliferate to enhance tissue repair and resolution. Here, we find that a previously elucidated nucleotide ‘cargo’ proliferation pathway that increases Myc mRNA is complemented by efferocytosis-induced lactate, which stabilizes Myc protein through SIRT1-mediated Myc protein deacetylation.

Iron is shown to have a central role in senescence, both by triggering senescence and through its accumulation in senescent cells, which is driving the senescence-associated secretory phenotype and, in turn, promotes fibrogenesis.

The authors present an overview of the metabolism and pleiotropic actions of ketone bodies, summarizing their endogenous sources, signalling mechanisms and systemic metabolic effects.

In this study, Papalazarou et al. screen the solute carrier family and identify candidates involved of serine transport in colorectal cancer cells. They further characterize cytosolic SLC6A14 and mitochondrial SLC25A15 as mediators of adequate serine supply to sustain cancer cell proliferation.

In a two-part randomized phase 2a trial in men and women with overweight or obesity and type 2 diabetes mellitus, cotadutide promoted greater reductions in liver glycogen and fat than placebo and liraglutide.

We demonstrated increased phospholipid peroxidation due to the formation of monolysocardiolipin–cytochrome c complexes in tafazzin-deficient models of Barth syndrome. We found that a specific anti-peroxidase agent inhibited this complex and improved mitochondrial respiration. Thus, targeting the deleterious peroxidase activity offers a potential therapeutic approach to treat Barth syndrome.

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.

Shoop et al. develop mitoARCUS, a mitochondria-targeted nuclease with high specificity, to correct a relatively common pathogenic mtDNA mutation, allowing for beneficial shifts in heteroplasmy while reducing nuclear off-target gene editing.

This Review discusses the role of mitophagy in cellular and organismal health and disease, with a specific focus on human ageing and evidence obtained in clinical studies.

Efferocytosis-induced macrophage proliferation is supported by increased non-canonical upregulation of glycolysis. Ngai, Schilperoort and Tabas provide mechanistic insight to understand how glycolysis-derived lactate contributes to this process by stabilizing MYC via extracellular signalling.

Hildreth et al. show that during diet-induced obesity, conventional type 1 dendritic cells (cDC1s) in white adipose tissue (WAT) take up DNA-containing apoptotic bodies from adipocytes, which triggers STING-dependent interleukin-12 production from cDC1s, contributing to WAT inflammation in mice.

In this study, Kagan et al. highlight the relevance of adequate cardiolipin homeostasis by offering mechanistic insight into the pathogenesis of Barth syndrome. The study shows how altered accumulation of mono-lyso-cardiolipin, one of the derivatives of the mitochondrial lipid cardiolipin, forms an anomalous peroxidase complex with cytochrome c, thus leading to increased oxidation of polyunsaturated phospholipids.

In 1923, Otto Warburg published his landmark study, in which he described his seminal observations related to metabolic shifts in cancer, often referred to as the Warburg effect. His work laid the foundation for an understanding of how metabolic reconfiguration contributes to cancer onset and progression. Several researchers in the field share their thoughts on what this discovery means to them and how it has inspired their scientific journey.

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.

This work identifies a role for Drp1-dependent mitochondrial fission for promoting stress susceptibility in male mice.

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.

Kovatcheva et al. show that vitamin B₁₂ improves the efficiency of in vivo reprogramming and tissue repair through its functions in one-carbon metabolism and epigenetic modulation.

Linder et al. show how cancer cells reduce proline biosynthesis through P5CS to cope with glutamine starvation.