Precise connectivity between specific neurons is essential for the formation of the complex neural circuitry necessary for executing intricate motor behaviors and higher cognitive functions. While trans interactions between synaptic surface proteins have emerged as crucial elements in orchestrating the assembly of neural circuits, the proteins involved in neuronal wiring remain largely unknown. Here, we uncover that the neurexin family of genes enables olfactory sensory neuron (OSN) axons to form appropriate connections with their mitral/tufted (M/T) cell synaptic partners within the olfactory system. Neurexins, which are differentially expressed within distinct populations of OSNs, synergistically cooperate to regulate axonal sorting to designated glomeruli. This process is facilitated through the interactions of neurexins with their postsynaptic partners, which have distinct expression patterns in M/T cells. Our findings suggest a mechanism underpinning the precise assembly of olfactory neural circuits, driven by the trans interaction between neurexins and their ligands.

Uridine is the ubiquitous nucleoside form of the RNA base uracil. It occupies a prominent ‘hub’ position in energy metabolism; for example, it is metabolically linked to de novo pyrimidine biosynthesis and glycolysis and biologically linked to diverse processes, such as RNA synthesis/degradation and glycosylation. It is a vital interorgan ‘currency’ nutrient readily imported by mammalian cells, and its supplementation can exert both cytoprotective and toxic effects, for which the underlying mechanisms are poorly understood. Importantly, it is a route by which the decay of RNA can be repurposed as an alternative fuel source under nutrient-limiting conditions to aid in tumor initiation, development and metastasis. Here we explain how the upstream inputs and downstream metabolic fates of uridine influence cancer traits and illustrate both established and hypothetical strategies targeting uridine metabolism for cancer therapy. Uridine is a crucial molecule in our bodies, involved in many biological processes. This study explores how cancer cells use uridine and how its biosynthetic pathway might be targeted for cancer therapy. Uridine circulates in the blood and is produced mainly in the liver. Cells take up uridine and convert it into other molecules, such as uridine monophosphate, that are essential for cell growth and survival. The study highlights that uridine can support cancer cell growth, especially when glucose is scarce, by providing an alternative energy source. Various methods have been used to study the roles of uridine in cancer, including examining how it is metabolized and how it affects cancer cell metabolism such as glycolysis, and found that disrupting uridine metabolism could potentially hinder cancer cell growth. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.

During metastasis, cancer cells detach from the primary tumor, circulate through the bloodstream, and establish themselves at distant sites, facing increased levels of reactive oxygen species that act as significant barriers to metastatic progression. Adapting to and surviving in these high reactive oxygen species environments are thus crucial for successful metastasis. A recent study by Nease and colleagues identified FTSJ1 as the methyltransferase responsible for methylation of the U34 position wobble uridine modification of selenocysteine (Sec) tRNA. This methylation enables efficient Sec insertion, leading to increased translation of a subset of stress-responsive selenoproteins that combat the oxidative stress encountered during the metastatic process. This study establishes FTSJ1 as an essential redox regulator during metastasis through its role in enhancing Sec insertion efficiency and introduces a potential therapeutic strategy against metastasis.

The canonical biological function of selenium is in the production of selenocysteine residues of selenoproteins, and this forms the basis for its role as an essential antioxidant and cytoprotective micronutrient. Here we demonstrate that, via its metabolic intermediate hydrogen selenide, selenium reduces ubiquinone in the mitochondria through catalysis by sulfide quinone oxidoreductase. Through this mechanism, selenium rapidly protects against lipid peroxidation and ferroptosis in a timescale that precedes selenoprotein production, doing so even when selenoprotein production has been eliminated. Our findings identify a regulatory mechanism against ferroptosis that implicates sulfide quinone oxidoreductase and expands our understanding of selenium in biology.

Precise connectivity between specific neurons is essential for the formation of the complex neural circuitry necessary for executing intricate motor behaviors and higher cognitive functions. While trans -interactions between synaptic membrane proteins have emerged as crucial elements in orchestrating the assembly of these neural circuits, the synaptic surface proteins involved in neuronal wiring remain largely unknown. Here, using unbiased single-cell transcriptomic and mouse genetic approaches, we uncover that the neurexin family of genes enables olfactory sensory neuron (OSNs) axons to form appropriate synaptic connections with their mitral and tufted (M/T) cell synaptic partners, within the mammalian olfactory system. Neurexin isoforms are differentially expressed within distinct populations of OSNs, resulting in unique pattern of neurexin expression that is specific to each OSN type, and synergistically cooperate to regulate axonal innervation, guiding OSN axons to their designated glomeruli. This process is facilitated through the interactions of neurexins with their postsynaptic partners, including neuroligins, which have distinct expression patterns in M/T cells. Our findings suggest a novel mechanism underpinning the precise assembly of olfactory neural circuits, driven by the trans -interaction between neurexins and their ligands.

This Figure show analysis of shATG5 tumors.

This Figure show alternative analysis for cell death in the tumors.

This Figure validates the tumor data in a second mouse experiment.

Supplementary Figure legends

This Figure validates the tumor growth data with another autophagy gene.

Identifying metabolic steps that are specifically required for the survival of cancer cells but are dispensable in normal cells remains a challenge 1 . Here we report a therapeutic vulnerability in a sugar nucleotide biosynthetic pathway that can be exploited in cancer cells with only a limited impact on normal cells. A systematic examination of conditionally essential metabolic enzymes revealed that UXS1, a Golgi enzyme that converts one sugar nucleotide (UDP-glucuronic acid, UDPGA) to another (UDP-xylose), is essential only in cells that express high levels of the enzyme immediately upstream of it, UGDH. This conditional relationship exists because UXS1 is required to prevent excess accumulation of UDPGA, which is produced by UGDH. UXS1 not only clears away UDPGA but also limits its production through negative feedback on UGDH. Excess UDPGA disrupts Golgi morphology and function, which impedes the trafficking of surface receptors such as EGFR to the plasma membrane and diminishes the signalling capacity of cells. UGDH expression is elevated in several cancers, including lung adenocarcinoma, and is further enhanced during chemoresistant selection. As a result, these cancer cells are selectively dependent on UXS1 for UDPGA detoxification, revealing a potential weakness in tumours with high levels of UGDH.

This Figure validates Beclin 1 regulation of HRS phosphorylation.

In inborn errors of metabolism, such as amino acid breakdown disorders, loss of function mutations in metabolic enzymes within the catabolism pathway lead to an accumulation of the catabolic intermediate that is the substrate of the mutated enzyme. In patients of such disorders, dietarily restricting the amino acid(s) to prevent the formation of these catabolic intermediates has a therapeutic or even entirely preventative effect. This demonstrates that the pathology is due to a toxic accumulation of enzyme substrates rather than the loss of downstream products. Here, we provide an overview of amino acid metabolic disorders from the perspective of the 'toxic metabolites' themselves, including their mechanism of toxicity and whether they are involved in the pathology of other disease contexts as well. In the research literature, there is often evidence that such metabolites play a contributing role in multiple other nonhereditary (and more common) disease conditions, and these studies can provide important mechanistic insights into understanding the metabolite-induced pathology of the inborn disorder. Furthermore, therapeutic strategies developed for the inborn disorder may be applicable to these nonhereditary disease conditions, as they involve the same toxic metabolite. We provide an in-depth illustration of this cross-informing concept in two metabolic disorders, methylmalonic acidemia and hyperammonemia, where the pathological metabolites methylmalonic acid and ammonia are implicated in other disease contexts, such as aging, neurodegeneration, and cancer, and thus there are opportunities to apply mechanistic or therapeutic insights from one disease context towards the other. Additionally, we expand our scope to other metabolic disorders, such as homocystinuria and nonketotic hyperglycinemia, to propose how these concepts can be applied broadly across different inborn errors of metabolism and various nonhereditary disease conditions.

The production of selenoproteins in cancer cells is dependent on uptake of selenium and processing via the selenocysteine biosynthesis pathway. Both the uptake and processing of selenium has recently shown to be upregulated in subsets of cancer cells due to their increased expression of xCT transporter, and the resulting increased expression of selenoproteins such as GPX4 can play multiple roles in cancer cells such as providing protection against ferroptotic insults. Here, we describe a set of protocols designed to measure this process in cancer cell culture—the measurement of xCT transporter expression and activity, the intracellular uptake of selenium in cancer cells, and the expression of selenoproteins as the final functional readout of this process. The successful measurement of xCT requires non-denaturing western blotting of xCT subunits, while its activity is determined by the measurement of reduced thiol groups that accumulate over time, as determined by Ellman's reagent. Selenium uptake is determined by supplementing a selenium source and then measuring total intracellular selenium levels, which is determined from digested cellular material using a reactive fluorescent probe or via inductively coupled plasma mass spectrometry. Finally, specific tips for efficiently determining the expression level of a set of “indicator” selenoproteins is provided. These parameters allow one to determine the “selenophilicity” of cells, i.e., the ability of cells to utilize selenite to upregulate their selenoprotein production and thus antioxidant defenses.

Sphingolipids play important signaling and structural roles in cells. Here, we find that during de novo sphingolipid biosynthesis, a toxic metabolite is formed with critical implications for cancer cell survival. The enzyme catalyzing the first step in this pathway, serine palmitoyltransferase complex (SPT), is upregulated in breast and other cancers. SPT is dispensable for cancer cell proliferation, as sphingolipids can be salvaged from the environment. However, SPT activity introduces a liability as its product, 3-ketodihydrosphingosine (3KDS), is toxic and requires clearance via the downstream enzyme 3-ketodihydrosphingosine reductase (KDSR). In cancer cells, but not normal cells, targeting KDSR induces toxic 3KDS accumulation leading to endoplasmic reticulum (ER) dysfunction and loss of proteostasis. Furthermore, the antitumor effect of KDSR disruption can be enhanced by increasing metabolic input (via high-fat diet) to allow greater 3KDS production. Thus, de novo sphingolipid biosynthesis entails a detoxification requirement in cancer cells that can be therapeutically exploited.

Growth differentiation factor 15 (GDF15) is a multifunctional protein associated with energy homeostasis and body weight regulation. GDF15 has emerged as an attractive therapeutic target to treat obesity-related metabolic disorders. GDF15 reduces food intake with a unique mode of action via its receptor GDNF family receptor α-like (GFRAL) and the co-receptor RET. YH34160 is an engineered GDF15 variant-Fc fusion protein to have extended half-life and potent functional activity by enhancing binding affinity to GDF15 receptors (GFRAL/RET) . Based on rodent and monkey pharmacokinetic (PK) data, YH34160 is expected to have an optimal PK profile for once-weekly dosing in humans. In efficacy studies using obese mouse models, YH34160 demonstrated a potent and sustained weight-lowering effect. After a single subcutaneous injection in diet-induced obese (DIO) mice, YH34160-treated groups showed sustained and dose-dependent body weight (BW) reduction compared to long-acting glucagon like peptide-1 receptor agonist (GLP-1RA) . Following a 6-week multiple-dose study in DIO mice, YH34160-treated groups exhibited a greater and more prolonged BW loss compared to the group of GLP-1RA. Marked BW reduction and improved lipid profile by YH34160 were also proved in leptin-deficient (ob/ob) mice compared to GLP-1RA. In addition, YH34160 caused significantly better anti-obesity effects, and a much more improved metabolic profile than that of albumin-GDF15, and dual GLP-1/Glucagon receptor agonist. Interestingly, YH34160 in combination with GLP-1RA or dual GLP-1/glucose-dependent insulinotropic polypeptide receptor agonist (GIPRA) achieved more potent and greater BW loss compared to each mono-treated group. Overall, these findings indicate that YH34160 would be a promising therapeutic candidate, as well as in combination with GLP-1-based therapeutics, for the treatment of obesity and obesity-related comorbidities. Disclosure S. Lim: None. D. Kim: None. J. Yang: None. M. Ju: None. S. Kim: None. B. Sim: None. J. Kim: None. S. Oh: Employee; Yuhan, Stock/Shareholder; Yuhan.

In a metabolic pathway, a series of metabolites are formed then chemically converted to the next one along the pathway. When this chain of events is broken, such as due to mutation of a pathway enzyme, a massive accumulation of a metabolite can occur and can have deleterious consequences, especially if the metabolite has toxic properties. Here, we describe our recent efforts to identify such toxic metabolites in a systemic manner, and examine their relevance in diseases. When a metabolic pathway is overactive in a cancer cell, blocking enzymes which process a toxic intermediate within that pathway can result in cancer cell selective toxic metabolite accumulation and poisoning, a highly attractive therapeutic strategy. We demonstrate as proofs of principles of this approach, manipulation of the selenocysteine biosynthesis pathway and the de novo sphingolipid biosynthesis pathway, for cancer therapy. We will also discuss how toxic metabolite accumulation can be contributing factors in other such as neurodegenerative disorders, and how metabolic pathway manipulation may be considered as a therapeutic strategy.