A5005463098- Cancer, Hypoxia, and Metabolism
- Mitochondrial Function and Pathology
- Metabolism and Genetic Disorders
- Metabolomics and Mass Spectrometry Studies
- Microbial Metabolic Engineering and Bioproduction
- Adipose Tissue and Metabolism
- ATP Synthase and ATPases Research
- Cardiovascular Function and Risk Factors
- Cardiac Ischemia and Reperfusion
- Diet and metabolism studies
- Epigenetics and DNA Methylation
- Bioinformatics and Genomic Networks
- Pancreatic function and diabetes
- Metabolism, Diabetes, and Cancer
- Fuel Cells and Related Materials
- Immune cells in cancer
- RNA Research and Splicing
- Immune Cell Function and Interaction
- Analytical Chemistry and Chromatography
- Mass Spectrometry Techniques and Applications
- Biochemical Acid Research Studies
- Advanced Proteomics Techniques and Applications
- Cancer Research and Treatments
- Heart Failure Treatment and Management
- Redox biology and oxidative stress
University of Utah
2019-2024
Cornell University
2014-2019
Duke University
2018-2019
King Abdullah International Medical Research Center
2016-2017
King Faisal Specialist Hospital & Research Centre
2009-2010
Aerobic glycolysis or the Warburg Effect (WE) is characterized by increased metabolism of glucose to lactate. It remains unknown what quantitative changes activity are necessary and sufficient for this phenotype. We developed a computational model an integrated analysis using metabolic control (MCA), metabolomics data, statistical simulations. identified confirmed novel mode regulation specific aerobic where flux through GAPDH, enzyme separating lower upper glycolysis, rate-limiting step in...
Metabolic networks are interconnected and influence diverse cellular processes. The protein-metabolite interactions that mediate these frequently low affinity challenging to systematically discover. We developed mass spectrometry integrated with equilibrium dialysis for the discovery of allostery (MIDAS) identify such interactions. Analysis 33 enzymes from human carbohydrate metabolism identified 830 interactions, including known regulators, substrates, products as well previously unreported...
Glucose metabolism links metabolic status to protein acetylation. However, it remains poorly understood what extent do features of glucose contribute acetylation and whether the process can be dynamically quantitatively regulated by differing rates glycolysis.Here, we show that titratable glycolysis with corresponding changes in levels glycolytic intermediates result a graded remodeling bulk metabolome resulted gradual total histone levels. Dynamic were found most strongly correlated acetyl...
Efforts to target glutamine metabolism for cancer therapy have focused on the glutaminase isozyme GLS. The importance of other isozyme, GLS2, in has remained unclear, and it been described as a tumor suppressor some contexts. Here, we report that GLS2 is upregulated essential luminal-subtype breast tumors, which account >70% incidence. We show expression elevated by GATA3 cells but suppressed promoter methylation basal-subtype cells. Although luminal cancers resist GLS-selective inhibitors,...
Mitochondrial membrane potential directly powers many critical functions of mitochondria, including ATP production, mitochondrial protein import, and metabolite transport. Its loss is a cardinal feature aging diseases, cells closely monitor as an indicator health. Given its central importance, it logical that would modulate in response to demand environmental cues, but there has been little exploration this question. We report the Sit4 phosphatase yeast increases potential, both by inducing...
Carbohydrates and lipids provide the majority of substrates to fuel mitochondrial oxidative phosphorylation. Metabolic inflexibility, defined as an impaired ability switch between these fuels, is implicated in a number metabolic diseases. Here, we explore mechanism by which physical inactivity promotes inflexibility skeletal muscle. We developed mouse model sedentariness, small cage (SMC), that, unlike other classic models disuse mice, faithfully recapitulated responses that occur humans....
The clinical therapy for treating acute myocardial infarction is primary percutaneous coronary intervention (PPCI). PPCI effective at reperfusing the heart, however rapid re-introduction of blood can cause ischemia-reperfusion (I/R). Reperfusion injury responsible up to half final damage, but there are no pharmacological interventions reduce I/R. We previously demonstrated that inhibiting monocarboxylate transporter 4 (MCT4) and re-directing pyruvate towards oxidation blunt hypertrophy....
Metabolic pathways regulate T cell development and function, but many remain understudied. Recently, the mitochondrial pyruvate carrier (MPC) was identified as transporter that mediates entry into mitochondria, promoting oxidation. Here we find deleting Mpc1, an obligate MPC subunit, in hematopoietic system results a specific reduction peripheral αβ numbers. MPC1-deficient cells have defective thymic at β-selection, intermediate single positive (ISP)-to-double-positive (DP), selection steps....
The fate of pyruvate is a defining feature in many cell types. One major mitochondrial entry via the carrier (MPC). We found that diffuse large B lymphomas (DLBCLs) consume glutamate-pyruvate transaminase 2 to enable α-ketoglutarate production as part glutaminolysis. This led us discover glutamine exceeds carbon source for tricarboxylic acid cycle DLBCLs. As result, MPC inhibition decreased glutaminolysis DLBCLs, opposite previous observations other also or genetic depletion DLBCL...
Diabetic cardiomyopathy, an increasingly global epidemic and a major cause of heart failure with preserved ejection fraction (HFpEF), is associated hyperglycemia, insulin resistance, intra-cardiomyocyte calcium mishandling. Here we identify that, in db/db mice type 2 diabetes induced HFpEF, abnormal remodeling cardiomyocyte transverse-tubule microdomains occurs downregulation the membrane scaffolding protein cardiac bridging integrator 1 (cBIN1). Transduction cBIN1 by AAV9 gene therapy can...
Abstract Metabolism is intertwined with various cellular processes, including controlling cell fate, influencing tumorigenesis, participating in stress responses and more. a complex, interdependent network, local perturbations can have indirect effects that are pervasive across the metabolic network. Current analytical technical limitations long created bottleneck data interpretation. To address these shortcomings, we developed Metaboverse, user-friendly tool to facilitate exploration...
Metabolite profiling has been a valuable asset in the study of metabolism health and disease. However, current platforms have different limiting factors, such as labor intensive sample preparations, low detection limits, slow scan speeds, method optimization for each metabolite, inability to measure both positively negatively charged ions single experiments. Therefore, novel metabolomics protocol could advance studies. Amide-based hydrophilic chromatography enables polar metabolite analysis...
The established clinical therapy for the treatment of acute myocardial infarction is primary percutaneous coronary intervention (PPCI) to restore blood flow ischemic myocardium. PPCI effective at reperfusing myocardium, however rapid re-introduction oxygenated also can cause ischemia-reperfusion (I/R) injury. Reperfusion injury culprit up half final damage, but there are no interventions reduce I/R We previously demonstrated that inhibiting lactate exporter, monocarboxylate transporter 4...
Abstract Metabolism is highly interconnected and also has profound effects on other cellular processes. However, the interactions between metabolites proteins that mediate this connectivity are frequently low affinity difficult to discover, hampering our understanding of important area biochemistry. Therefore, we developed MIDAS platform, which can identify protein-metabolite with great sensitivity. We analyzed 33 enzymes from central carbon metabolism identified 830 were mostly novel, but...
Abstract Lactate is the highest turnover circulating metabolite in mammals. While traditionally viewed as a waste product, lactate an important energy source for many organs, but first must be oxidized to pyruvate entry into tricarboxylic acid cycle (TCA cycle). This reaction thought occur cytosol, with subsequently transported mitochondria via mitochondrial carrier (MPC). Using 13 C stable isotope tracing, we demonstrated that myocardial tissue of mice even when MPC genetically deleted....
Pyruvate occupies a central node in carbohydrate metabolism such that how it is produced and consumed can optimize cell for energy production or biosynthetic capacity. This has been primarily studied proliferating cells, but observations from the post-mitotic Drosophila fat body led us to hypothesize pyruvate fate might dictate rapid growth observed this organ during development. Indeed, we demonstrate augmented mitochondrial import prevented cells vivo as well cultured mammalian hepatocytes...
Metabolite profiling has been a valuable asset in the study of metabolism health and disease. However, current platforms have different limiting factors, such as labor intensive sample preparations, low detection limits, slow scan speeds, method optimization for each metabolite, inability to measure both positively negatively charged ions single experiments. Therefore, novel metabolomics protocol could advance studies. Amide-based hydrophilic chromatography enables polar metabolite analysis...
The ability of a cell to exhibit anchorage independent growth is hallmark cancer, and has been extensively investigated in hopes finding new therapeutic strategies. In particular, the processes that give rise support this dysregulated phenotype, which allows cells proliferate absence survival signals resulting from their attachment basement membrane, interest. contribution oncogenes tumor suppressors on well studied; however, alterations cellular metabolism process are much less defined....
Metabolism forms a complex, interdependent network, and perturbations can have indirect effects that are pervasive. Identifying these patterns their consequences is difficult, particularly when the occur across canonical pathways, difficulties long acted as bottleneck in metabolic data analysis. This challenge compounded by technical limitations metabolomics approaches garner incomplete datasets. Current network-based tools generally utilize pathway-level analysis lacking granular resolution...