Succinate dehydrogenase activity supports de novo purine synthesis.

The de novo purine synthesis pathway is fundamental for nucleic acid production and cellular energetics, yet the role of mitochondrial metabolism in modulating this process remains underexplored. In many cancers, metabolic reprogramming supports rapid proliferation and survival, but the specific contributions of the tricarboxylic acid (TCA) cycle enzymes to nucleotide biosynthesis are not fully understood. Here, we demonstrate that the TCA cycle enzyme succinate dehydrogenase (SDH) is essential for maintaining optimal de novo purine synthesis in normal and cancer cells.

Lysine vitcylation is a vitamin C-derived protein modification that enhances STAT1-mediated immune response.

Vitamin C (vitC) is essential for health and shows promise in treating diseases like cancer, yet its mechanisms remain elusive. Here, we report that vitC directly modifies lysine residues to form "vitcyl-lysine"-a process termed vitcylation. Vitcylation occurs in a dose-, pH-, and sequence-dependent manner in both cell-free systems and living cells.

HHIP protein interactions in lung cells provide insight into COPD pathogenesis.

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide. The primary causes of COPD are environmental, including cigarette smoking; however, genetic susceptibility also contributes to COPD risk. Genome-Wide Association Studies (GWASes) have revealed more than 80 genetic loci associated with COPD, leading to the identification of multiple COPD GWAS genes.

Epstein-Barr virus-driven cardiolipin synthesis sustains metabolic remodeling during B cell transformation.

The Epstein-Barr virus (EBV) infects nearly 90% of adults globally and is linked to over 200,000 annual cancer cases. Immunocompromised individuals from conditions such as primary immune disorders, HIV, or posttransplant immunosuppressive therapies are particularly vulnerable because of EBV's transformative capability. EBV remodels B cell metabolism to support energy, biosynthetic precursors, and redox equivalents necessary for transformation.

Systemic regulation of retinal medium-chain fatty acid oxidation repletes TCA cycle flux in oxygen-induced retinopathy.

Activation of anaplerosis takes away glutamine from the biosynthetic pathways to the energy-producing TCA cycle. Especially, induction of hyperoxia driven anaplerosis in neurovascular tissues such as the retina during early stages of development could deplete biosynthetic precursors from newly proliferating endothelial cells impeding physiological angiogenesis and leading to vasoobliteration. Using an oxygen-induced retinopathy (OIR) mouse model, we investigated the metabolic differences between OIR-resistant BALB/cByJ and OIR susceptible C57BL/6J strains at system levels to understand the molecular underpinnings that potentially contribute to hyperoxia-induced vascular abnormalities in the neural retina.

Epstein-Barr Virus Latent Membrane Protein 1 Subverts IMPDH pathways to drive B-cell oncometabolism.

Unlabelled: Epstein-Barr virus (EBV) is associated with multiple types of cancers, many of which express the key viral oncoprotein Latent Membrane Protein 1 (LMP1). LMP1 is the only EBV-encoded protein whose expression is sufficient to transform both epithelial and B-cells. Although metabolism reprogramming is a cancer hallmark, much remains to be learned about how LMP1 alters lymphocyte oncometabolism.

Parallel phosphoproteomics and metabolomics map the global metabolic tyrosine phosphoproteome.

Tyrosine phosphorylation of metabolic enzymes is an evolutionarily conserved posttranslational modification that facilitates rapid and reversible modulation of enzyme activity, localization, or function. Despite the high abundance of tyrosine phosphorylation events detected on metabolic enzymes in high-throughput mass spectrometry-based studies, functional characterization of tyrosine phosphorylation sites has been limited to a subset of enzymes. Since tyrosine phosphorylation is dysregulated across human diseases, including cancer, understanding the consequences of metabolic enzyme tyrosine phosphorylation events is critical for informing disease biology and therapeutic interventions.

Methylmalonic acid induces metabolic abnormalities and exhaustion in CD8 T cells to suppress anti-tumor immunity.

Systemic levels of methylmalonic acid (MMA), a byproduct of propionate metabolism, increase with age and MMA promotes tumor progression via its direct effects in tumor cells. However, the role of MMA in modulating the tumor ecosystem remains to be investigated. The proliferation and function of CD8 T cells, key anti-tumor immune cells, declines with age and in conditions of vitamin B12 deficiency, which are the two most well-established conditions that lead to increased systemic levels of MMA.

Integrated Multi-Omics Analysis of Cerebrospinal Fluid in Postoperative Delirium.

Preoperative risk biomarkers for delirium may aid in identifying high-risk patients and developing intervention therapies, which would minimize the health and economic burden of postoperative delirium. Previous studies have typically used single omics approaches to identify such biomarkers. Preoperative cerebrospinal fluid (CSF) from the Healthier Postoperative Recovery study of adults ≥ 63 years old undergoing elective major orthopedic surgery was used in a matched pair delirium case-no delirium control design.

Unique tau- and synuclein-dependent metabolic reprogramming in neurons distinct from normal aging.

Neuronal cells are highly specialized cells and have a specific metabolic profile to support their function. It has been demonstrated that the metabolic profiles of different cells/tissues undergo significant reprogramming with advancing age, which has often been considered a contributing factor towards aging-related diseases including Alzheimer's (AD) and Parkinson's (PD) diseases. However, it is unclear if the metabolic changes associated with normal aging predispose neurons to disease conditions or a distinct set of metabolic alterations happen in neurons in AD or PD which might contribute to disease pathologies.

Derangement in Nicotinamide Adenine Dinucleotide Metabolism is Observed During Acute Kidney Injury Among Male Agricultural Workers at Risk for Mesoamerican Nephropathy.

Introduction: Mesoamerican nephropathy (MeN) is a chronic kidney disease (CKD) which may be caused by recurrent acute kidney injury (AKI). We investigated urinary quinolinate-to-tryptophan ratio (Q/T), a validated marker of nicotinamide adenine dinucleotide (NAD+) biosynthesis that is elevated during ischemic and inflammatory AKI, in a sugarcane worker population in Nicaragua with high rates of MeN.

Methods: Among 693 male sugarcane workers studied, we identified 45 who developed AKI during the harvest season.

The CTLH Ubiquitin Ligase Substrates ZMYND19 and MKLN1 Negatively Regulate mTORC1 at the Lysosomal Membrane.

Most Epstein-Barr virus-associated gastric carcinoma (EBVaGC) harbor non-silent mutations that activate phosphoinositide 3 kinase (PI3K) to drive downstream metabolic signaling. To gain insights into PI3K/mTOR pathway dysregulation in this context, we performed a human genome-wide CRISPR/Cas9 screen for hits that synergistically blocked EBVaGC proliferation together with the PI3K antagonist alpelisib. Multiple subunits of carboxy terminal to LisH (CTLH) E3 ligase, including the catalytic MAEA subunit, were among top screen hits.

Identification of high sugar diet-induced dysregulated metabolic pathways in muscle using tissue-specific metabolic models in .

Individual tissues perform highly specialized metabolic functions to maintain whole-body homeostasis. Although serves as a powerful model for studying human metabolic diseases, a lack of tissue-specific metabolic models makes it challenging to quantitatively assess the metabolic processes of individual tissues and disease models in this organism. To address this issue, we reconstructed 32 tissue-specific genome-scale metabolic models (GEMs) using pseudo-bulk single cell transcriptomics data, revealing distinct metabolic network structures across tissues.

Epstein-Barr-Virus-Driven Cardiolipin Synthesis Sustains Metabolic Remodeling During B-cell Lymphomagenesis.

Epstein-Barr Virus (EBV) is associated with a range of B-cell malignancies, including Burkitt, Hodgkin, post-transplant, and AIDS-related lymphomas. Studies highlight EBV's transformative capability to induce oncometabolism in B-cells to support energy, biosynthetic precursors, and redox equivalents necessary for transition from quiescent to proliferation. Mitochondrial dysfunction presents an intrinsic barrier to EBV B-cell immortalization.

HHIP protein interactions in lung cells provide insight into COPD pathogenesis.

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide. The primary causes of COPD are environmental, including cigarette smoking; however, genetic susceptibility also contributes to COPD risk. Genome-Wide Association Studies (GWASes) have revealed more than 80 genetic loci associated with COPD, leading to the identification of multiple COPD GWAS genes.

Inactivation of adenosine receptor 2A suppresses endothelial-to-mesenchymal transition and inhibits subretinal fibrosis in mice.

Anti-vascular endothelial growth factor therapy has had a substantial impact on the treatment of choroidal neovascularization (CNV) in patients with neovascular age-related macular degeneration (nAMD), the leading cause of vision loss in older adults. Despite treatment, many patients with nAMD still develop severe and irreversible visual impairment because of the development of subretinal fibrosis. We recently reported the anti-inflammatory and antiangiogenic effects of inhibiting the gene encoding adenosine receptor 2A (), which has been implicated in cardiovascular disease.

CDK6 inhibits de novo lipogenesis in white adipose tissues but not in the liver.

Increased de novo lipogenesis (DNL) in white adipose tissue is associated with insulin sensitivity. Under both Normal-Chow-Diet and High-Fat-Diet, mice expressing a kinase inactive Cyclin-dependent kinase 6 (Cdk6) allele (K43M) display an increase in DNL in visceral white adipose tissues (VAT) as compared to wild type mice (WT), accompanied by markedly increased lipogenic transcriptional factor Carbohydrate-responsive element-binding proteins (CHREBP) and lipogenic enzymes in VAT but not in the liver. Treatment of WT mice under HFD with a CDK6 inhibitor recapitulates the phenotypes observed in K43M mice.

A carboxy-terminal ubiquitylation site regulates androgen receptor activity.

Degradation of unliganded androgen receptor (AR) in prostate cancer cells can be prevented by proteasome inhibition, but this is associated with only modest increases in polyubiquitylated AR. An inhibitor (VLX1570) of the deubiquitylases associated with the proteasome did not increase ubiquitylation of unliganded AR, indicating that AR is not targeted by these deubiquitylases. We then identified a series of AR ubiquitylation sites, including a not previously identified site at K911, as well as methylation sites and previously identified phosphorylation sites.

Myeloid PFKFB3-mediated glycolysis promotes kidney fibrosis.

Excessive renal fibrosis is a common pathology in progressive chronic kidney diseases. Inflammatory injury and aberrant repair processes contribute to the development of kidney fibrosis. Myeloid cells, particularly monocytes/macrophages, play a crucial role in kidney fibrosis by releasing their proinflammatory cytokines and extracellular matrix components such as collagen and fibronectin into the microenvironment of the injured kidney.

PRMT1 orchestrates with SAMTOR to govern mTORC1 methionine sensing via Arg-methylation of NPRL2.

Methionine is an essential branch of diverse nutrient inputs that dictate mTORC1 activation. In the absence of methionine, SAMTOR binds to GATOR1 and inhibits mTORC1 signaling. However, how mTORC1 is activated upon methionine stimulation remains largely elusive.

Molecular EPISTOP, a comprehensive multi-omic analysis of blood from Tuberous Sclerosis Complex infants age birth to two years.

We present a comprehensive multi-omic analysis of the EPISTOP prospective clinical trial of early intervention with vigabatrin for pre-symptomatic epilepsy treatment in Tuberous Sclerosis Complex (TSC), in which 93 infants with TSC were followed from birth to age 2 years, seeking biomarkers of epilepsy development. Vigabatrin had profound effects on many metabolites, increasing serum deoxycytidine monophosphate (dCMP) levels 52-fold. Most serum proteins and metabolites, and blood RNA species showed significant change with age.