A5070060453- Cancer, Hypoxia, and Metabolism
- Adipose Tissue and Metabolism
- Biochemical and Molecular Research
- Mitochondrial Function and Pathology
- RNA modifications and cancer
- Metabolism and Genetic Disorders
- Metabolism, Diabetes, and Cancer
- Metabolomics and Mass Spectrometry Studies
- Pancreatic function and diabetes
- Epigenetics and DNA Methylation
- Muscle metabolism and nutrition
- Diet and metabolism studies
- PI3K/AKT/mTOR signaling in cancer
- CRISPR and Genetic Engineering
- Endoplasmic Reticulum Stress and Disease
- Ferroptosis and cancer prognosis
- Cancer Genomics and Diagnostics
- Glioma Diagnosis and Treatment
- Selenium in Biological Systems
- Chemical Reactions and Isotopes
- Immune cells in cancer
- Trace Elements in Health
- Biochemical Acid Research Studies
- Sirtuins and Resveratrol in Medicine
- Prostate Cancer Treatment and Research
Massachusetts Institute of Technology
2020-2025
University of Massachusetts Chan Medical School
2023-2025
Whitehead Institute for Biomedical Research
2021-2025
UMass Memorial Medical Center
2023
Boston VA Research Institute
2020-2022
Harvard University
2016-2022
Howard Hughes Medical Institute
2020-2022
Broad Institute
2017-2021
University of Iowa
2020
Center for Cancer Research
2018
Cancer cells put ammonia back to work Ammonia, often considered a metabolic waste product, can be recycled build new amino acids. Rapidly proliferating produce extracellular nitrogen. Spinelli et al. used tracing of 15 N follow the fate and its incorporation into more than 200 components nitrogen metabolome (see Perspective by Dang). Accumulation enabled glutamate dehydrogenase function in reductive amination, which allowed from Experiments mice also showed glutamate, aspartate, proline....
Gain-of-function mutations in isocitrate dehydrogenase (IDH) human cancers result the production of d-2-hydroxyglutarate (d-2HG), an oncometabolite that promotes tumorigenesis through epigenetic alterations. The cancer cell-intrinsic effects d-2HG are well understood, but its tumor cell-nonautonomous roles remain poorly explored. We compared with enantiomer, l-2HG, and found tumor-derived was taken up by CD8+ T cells altered their metabolism antitumor functions acute reversible fashion....
Chemotherapy resistance is a major barrier to the treatment of triple-negative breast cancer (TNBC), and strategies circumvent are required. Using in vitro vivo metabolic profiling TNBC cells, we show that an increase abundance pyrimidine nucleotides occurs response chemotherapy exposure. Mechanistically, elevation induced by dependent on increased activity de novo synthesis pathway. Pharmacologic inhibition sensitizes cells genotoxic agents exacerbating DNA damage. Moreover, combined with...
For electrons to continuously enter and flow through the mitochondrial electron transport chain (ETC), they must ultimately land on a terminal acceptor (TEA), which is known be oxygen in mammals. Paradoxically, we find that complex I dihydroorotate dehydrogenase (DHODH) can still deposit into ETC when reduction impeded. Cells lacking accumulate ubiquinol, driving succinate (SDH) reverse enable deposition onto fumarate. Upon inhibition of reduction, fumarate sustains DHODH activities. Mouse...
Significance The mTORC1 eukaryotic cell growth regulator dynamically responds to changes in environmental nutrient levels. While many upstream regulators are known modulate activity, the full complement of these is unknown. Here, using a genome-wide FACS-based CRISPR-Cas9 screen, we identify almost all positive as well others. results our screens highlighted importance mitochondrial health regulation mTORC1, which led us investigate how stress impinges on signaling. Ultimately, found that...
Highlights•RQ is present in mitochondria isolated from certain mouse and human tissues•RQ carries electrons to fumarate as the electron acceptor, independently of O2 levels•The ETC can be reprogrammed RQ/fumarate pathway using genetic pharmacologic tools•Reprogramming mitigates hypoxia-induced damage vitro vivoSummaryUbiquinone (UQ), only known carrier mammalian transport chain (ETC), preferentially delivers terminal acceptor oxygen (O2). In hypoxia, ubiquinol (UQH2) diverts these onto...
The mechanistic target of rapamycin complex 1 (mTORC1) kinase controls growth in response to nutrients, including the amino acid leucine. In cultured cells, mTORC1 senses leucine through leucine-binding Sestrin proteins, but physiological functions and distribution Sestrin-mediated sensing mammals are unknown. We find that mice lacking Sestrin1 Sestrin2 cannot inhibit upon dietary deprivation suffer a rapid loss white adipose tissue (WAT) muscle. WAT is driven by aberrant activity fibroblast...
Obesity poses a global health challenge, demanding deeper understanding of adipose tissue (AT) and its mitochondria. This study describes the role mitochondrial protein Methylation-controlled J (MCJ/DnaJC15) in orchestrating brown (BAT) thermogenesis. Here we show how MCJ expression decreases during obesity, as evident human mouse samples. MCJKO mice, even without UCP1, fundamental thermogenic protein, exhibit elevated BAT Electron microscopy unveils changes morphology resembling activation....
Upon nutrient stimulation, pre-adipocytes undergo differentiation to transform into mature adipocytes capable of storing nutrients as fat. We profiled cellular metabolite consumption identify early metabolic drivers adipocyte differentiation. find that raises the uptake and numerous amino acids. In particular, branched-chain acid (BCAA) catabolism precedes promotes peroxisome proliferator-activated receptor gamma (PPARγ), a key regulator adipogenesis. adipogenesis, mitochondrial sirtuin...
Abstract Insulin receptor (IR) signaling is central to normal metabolic control and dysregulated in diseases such as type 2 diabetes. We report here that IR incorporated into dynamic clusters at the plasma membrane, cytoplasm nucleus of human hepatocytes adipocytes. stimulation promotes further incorporation these insulin-sensitive cells but not insulin-resistant cells, where both accumulation behavior are reduced. Treatment with metformin, a first-line drug used treat diabetes, can rescue...
Sirtuin 3 (SIRT3) is a NAD+-dependent deacetylase downregulated in aging and age-associated diseases such as cancer neurodegeneration high-fat diet (HFD)-induced metabolic disorders. Here, we performed small-molecule screen identified an unexpected vulnerability associated with SIRT3 loss. Azaserine, glutamine analog, was the top compound that inhibited growth proliferation of cells lacking SIRT3. Using stable isotope tracing glutamine, observed its increased incorporation into de novo...