A5024181231- Cancer, Hypoxia, and Metabolism
- Mitochondrial Function and Pathology
- Metabolomics and Mass Spectrometry Studies
- Adipose Tissue and Metabolism
- Metabolism, Diabetes, and Cancer
- Metabolism and Genetic Disorders
- Sirtuins and Resveratrol in Medicine
- RNA modifications and cancer
- Adrenal and Paraganglionic Tumors
- Cancer-related molecular mechanisms research
- ATP Synthase and ATPases Research
- Glioma Diagnosis and Treatment
- Immune Cell Function and Interaction
- Liver Disease Diagnosis and Treatment
- Acute Lymphoblastic Leukemia research
- Pancreatic function and diabetes
- Hormonal Regulation and Hypertension
- Epigenetics and DNA Methylation
- Organ Transplantation Techniques and Outcomes
- Iron Metabolism and Disorders
- Bioinformatics and Genomic Networks
- Autophagy in Disease and Therapy
- Biochemical and Molecular Research
- Ferroptosis and cancer prognosis
- PARP inhibition in cancer therapy
University of Birmingham
2016-2025
Max Planck Institute for Metabolism Research
2024
Genomics (United Kingdom)
2022
National Institutes of Health
2020
Yale University
2020
Harvard University
2020
Rockefeller University
2020
University of Pennsylvania
2019
King's College London
2018
The Francis Crick Institute
2018
Succinate dehydrogenase (SDH) and fumarate hydratase (FH) are components of the tricarboxylic acid (TCA) cycle tumor suppressors. Loss SDH or FH induces pseudohypoxia, a major tumor-supporting event, which is activation hypoxia-inducible factor (HIF) under normoxia. In SDH- FH-deficient cells, HIF due to HIF1alpha stabilization by succinate fumarate, respectively, either which, when in excess, inhibits HIFalpha prolyl hydroxylase (PHD). To reactivate PHD, we focused on its substrate,...
Nicotinamide adenine dinucleotide (NAD+) is modulated by conditions of metabolic stress and has been reported to decline with aging in preclinical models, but human data are sparse. riboside (NR) supplementation ameliorates dysfunction rodents. We aimed establish whether oral NR aged participants can increase the skeletal muscle NAD+ metabolome if it alter mitochondrial bioenergetics. supplemented 12 men 1 g per day for 21 days a placebo-controlled, randomized, double-blind, crossover trial....
The citric acid cycle (CAC) metabolite fumarate has been proposed to be cardioprotective; however, its mechanisms of action remain determined. To augment cardiac levels and assess fumarate's cardioprotective properties, we generated hydratase (Fh1) knockout (KO) mice. These fumarate-replete hearts were robustly protected from ischemia-reperfusion injury (I/R). compensate for the loss Fh1 activity, KO maintain ATP in part by channeling amino acids into CAC. In addition, stabilizing...
Abstract The tricarboxylic acid (TCA) cycle is a central metabolic pathway responsible for supplying reducing potential oxidative phosphorylation and anabolic substrates cell growth, repair proliferation. As such it thought to be essential proliferation tissue homeostasis. However, since the initial report of an inactivating mutation in TCA enzyme complex, succinate dehydrogenase (SDH) paraganglioma (PGL), has become clear that some cells tissues are not only able survive with truncated...
Hypoxia is one of the features poorly vascularised areas solid tumours but cancer cells can survive in these despite low oxygen tension. The adaptation to hypoxia requires both biochemical and genetic responses that culminate a metabolic rearrangement counter-balance decrease energy supply from mitochondrial respiration. understanding adaptations under could reveal novel pathways that, if targeted, would lead specific death hypoxic regions. In this study, we developed metabolomic analyses...
Intratumoral hypoxia and immunity have been correlated with patient outcome in various tumor settings. However, these factors are not currently considered for treatment selection head neck cancer (HNC) due to lack of validated biomarkers. Here we sought develop a hypoxia-immune classifier potential application prognostication prediction response targeted therapy.
BACKGROUND. Idiopathic intracranial hypertension (IIH) is a condition predominantly affecting obese women of reproductive age. Recent evidence suggests that IIH disease metabolic dysregulation, androgen excess, and an increased risk cardiovascular morbidity. Here we evaluate systemic adipose specific determinants the phenotype.
Succinate dehydrogenase (SDH) loss-of-function mutations drive succinate accumulation in tumor microenvironments, for example the neuroendocrine tumors pheochromocytoma (PC) and paraganglioma (PG). Control of innate immune cell activity by is described, but effects on T cells have not been interrogated. Here we report that exposure human CD4
Autophagy is a homeostatic process critical for cellular survival, and its malfunction implicated in human diseases including neurodegeneration. Loss of autophagy contributes to cytotoxicity tissue degeneration, but the mechanistic understanding this phenomenon remains elusive. Here, we generated autophagy-deficient (ATG5−/−) embryonic stem cells (hESCs), from which established neuronal platform investigate how loss affects survival. ATG5−/− neurons exhibit basal accompanied by metabolic...
Upon activation, T cells undergo metabolic reprogramming to meet the bioenergetic demands of clonal expansion and effector function. Because dysregulated cell cytokine production phenotypes coexist in chronic inflammatory disease, including rheumatoid arthritis (RA), we investigated whether cytokines released by differentiating amplified their changes. We found that tumor necrosis factor–α (TNF-α) human naïve CD4 + upon activation stimulated expression a transcriptome increased glycolysis,...
The identification of mutated metabolic enzymes in hereditary cancer syndromes has established a direct link between dysregulation and cancer. Mutations the Krebs cycle enzyme, fumarate hydratase (FH), predispose affected individuals to leiomyomas, renal cysts, cancers, though respective pathogenic roles mitochondrial cytosolic FH isoforms remain undefined. On basis comprehensive metabolomic analyses, we demonstrate that FH1-deficient cells tissues exhibit defects urea cycle/arginine...
Metabolic transformation in cancer is increasingly well understood. However, little known about the metabolic responses of cells that permit their survival different microenvironments. We have used a nuclear magnetic resonance based approach to monitor metabolism living primary chronic lymphoid leukemia (CLL) and interrogate real-time hypoxia. Our studies demonstrate considerable plasticity CLL cells. Despite being oxygenated blood, circulating are primed for hypoxia as measured by...
Since the discovery of mutations in isocitrate dehydrogenase 1 (IDH1) gliomas and other tumors, significant efforts have been made to gain a deeper understanding consequences this oncogenic mutation. One aspect neomorphic function IDH1 R132H enzyme that has received less attention is perturbation cellular redox homeostasis. Here, we describe biosynthetic pathway exhibited by cells expressing mutant IDH1. By virtue change homeostasis, IDH1-mutated synthesize excess glutamine-derived proline...
Brain tumours are the most common cause of cancer death in children. Molecular studies have greatly improved our understanding these but tumour metabolism is underexplored. Metabolites measured vivo been reported as prognostic biomarkers analysis surgically resected tissue allows a more extensive set metabolites to be aiding biomarker discovery and providing validation findings. In this study, were quantified across range paediatric brain using 1H-High-Resolution Magic Angle Spinning nuclear...