keyword
https://read.qxmd.com/read/38547260/pyrimidines-maintain-mitochondrial-pyruvate-oxidation-to-support-de-novo-lipogenesis
#1
JOURNAL ARTICLE
Umakant Sahu, Elodie Villa, Colleen R Reczek, Zibo Zhao, Brendan P O'Hara, Michael D Torno, Rohan Mishra, William D Shannon, John M Asara, Peng Gao, Ali Shilatifard, Navdeep S Chandel, Issam Ben-Sahra
Cellular purines, particularly adenosine 5'-triphosphate (ATP), fuel many metabolic reactions, but less is known about the direct effects of pyrimidines on cellular metabolism. We found that pyrimidines, but not purines, maintain pyruvate oxidation and the tricarboxylic citric acid (TCA) cycle by regulating pyruvate dehydrogenase (PDH) activity. PDH activity requires sufficient substrates and cofactors, including thiamine pyrophosphate (TPP). Depletion of cellular pyrimidines decreased TPP synthesis, a reaction carried out by TPP kinase 1 (TPK1), which reportedly uses ATP to phosphorylate thiamine (vitamin B1)...
March 29, 2024: Science
https://read.qxmd.com/read/38469353/characterization-of-hyperpolarization-activated-cyclic-nucleotide-gated-channels-in-oligodendrocytes
#2
JOURNAL ARTICLE
Kyle A Lyman, Ye Han, Andrew P Robinson, Samuel E Weinberg, Daniel W Fisher, Robert J Heuermann, Reagan E Lyman, Dong Kyu Kim, Andreas Ludwig, Navdeep S Chandel, Mark D Does, Stephen D Miller, Dane M Chetkovich
Mature oligodendrocytes (OLG) are the myelin-forming cells of the central nervous system. Recent work has shown a dynamic role for these cells in the plasticity of neural circuits, leading to a renewed interest in voltage-sensitive currents in OLG. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels and their respective current (I h ) were recently identified in mature OLG and shown to play a role in regulating myelin length. Here we provide a biochemical and electrophysiological characterization of HCN channels in cells of the oligodendrocyte lineage...
2024: Frontiers in Cellular Neuroscience
https://read.qxmd.com/read/38441967/cd8-t-cells-sustain-antitumor-response-by-mediating-crosstalk-between-adenosine-a2a-receptor-and-glutathione-gpx4
#3
JOURNAL ARTICLE
Siqi Chen, Jie Fan, Ping Xie, Jihae Ahn, Michelle Fernandez, Leah K Billingham, Jason Miska, Jennifer D Wu, Derek A Wainwright, Deyu Fang, Jeffrey A Sosman, Yong Wan, Yi Zhang, Navdeep S Chandel, Bin Zhang
Antitumor responses of CD8+ T cells are tightly regulated by distinct metabolic fitness. High levels of glutathione (GSH) are observed in the majority of tumors contributing to cancer progression and treatment resistance in part by preventing glutathione peroxidase 4 (GPX4) dependent ferroptosis. Here, we show the necessity of the adenosine A2A receptor (A2AR) signaling and the glutathione (GSH)-GPX4 axis in orchestrating metabolic fitness and survival of functionally competent CD8+ T cells. Activated CD8+ T cells treated ex vivo with simultaneous inhibition of A2AR and lipid peroxidation acquire a superior capacity to proliferate and persist in vivo, demonstrating a translatable means to prevent ferroptosis in adoptive cell therapy (ACT)...
March 5, 2024: Journal of Clinical Investigation
https://read.qxmd.com/read/38304969/a-drosophila-model-of-mitochondrial-disease-phenotypic-heterogeneity
#4
JOURNAL ARTICLE
Lucy Granat, Debbra Y Knorr, Daniel C Ranson, Ram Prosad Chakrabarty, Navdeep S Chandel, Joseph M Bateman
Mutations in genes that affect mitochondrial function cause primary mitochondrial diseases. Mitochondrial diseases are highly heterogeneous and even patients with the same mitochondrial disease can exhibit broad phenotypic heterogeneity, which is poorly understood. Mutations in subunits of mitochondrial respiratory complex I cause complex I deficiency, which can result in severe neurological symptoms and death in infancy. However, some complex I deficiency patients present with much milder symptoms. The most common nuclear gene mutated in complex I deficiency is the highly conserved core subunit NDUFS1...
February 2, 2024: Biology Open
https://read.qxmd.com/read/38299592/molecular-and-cellular-mechanisms-underlying-the-failure-of-mitochondrial-metabolism-drugs-in-cancer-clinical-trials
#5
JOURNAL ARTICLE
Karthik Vasan, Navdeep S Chandel
No abstract text is available yet for this article.
February 1, 2024: Journal of Clinical Investigation
https://read.qxmd.com/read/38168401/%C3%AE-synuclein-pathology-disrupts-mitochondrial-function-in-dopaminergic-and-cholinergic-neurons-at-risk-in-parkinson-s-disease
#6
Fanni F Geibl, Martin T Henrich, Zhong Xie, Enrico Zampese, Tatiana Tkatch, David L Wokosin, Elena Nasiri, Constantin A Grotmann, Valina L Dawson, Ted M Dawson, Navdeep S Chandel, Wolfgang H Oertel, D James Surmeier
BACKGROUND: Pathological accumulation of aggregated α-synuclein (aSYN) is a common feature of Parkinson's disease (PD). However, the mechanisms by which intracellular aSYN pathology contributes to dysfunction and degeneration of neurons in the brain are still unclear. A potentially relevant target of aSYN is the mitochondrion. To test this hypothesis, genetic and physiological methods were used to monitor mitochondrial function in substantia nigra pars compacta (SNc) dopaminergic and pedunculopontine nucleus (PPN) cholinergic neurons after stereotaxic injection of aSYN pre-formed fibrils (PFFs) into the mouse brain...
December 11, 2023: bioRxiv
https://read.qxmd.com/read/38134929/myeloid-cell-derived-creatine-in-the-hypoxic-niche-promotes-glioblastoma-growth
#7
JOURNAL ARTICLE
Aida Rashidi, Leah K Billingham, Andrew Zolp, Tzu-Yi Chia, Caylee Silvers, Joshua L Katz, Cheol H Park, Suzi Delay, Lauren Boland, Yuheng Geng, Steven M Markwell, Crismita Dmello, Victor A Arrieta, Kaylee Zilinger, Irene M Jacob, Aurora Lopez-Rosas, David Hou, Brandyn Castro, Alicia M Steffens, Kathleen McCortney, Jordain P Walshon, Mariah S Flowers, Hanchen Lin, Hanxiang Wang, Junfei Zhao, Adam Sonabend, Peng Zhang, Atique U Ahmed, Daniel J Brat, Dieter H Heiland, Catalina Lee-Chang, Maciej S Lesniak, Navdeep S Chandel, Jason Miska
Glioblastoma (GBM) is a malignancy dominated by the infiltration of tumor-associated myeloid cells (TAMCs). Examination of TAMC metabolic phenotypes in mouse models and patients with GBM identified the de novo creatine metabolic pathway as a hallmark of TAMCs. Multi-omics analyses revealed that TAMCs surround the hypoxic peri-necrotic regions of GBM and express the creatine metabolic enzyme glycine amidinotransferase (GATM). Conversely, GBM cells located within these same regions are uniquely specific in expressing the creatine transporter (SLC6A8)...
January 2, 2024: Cell Metabolism
https://read.qxmd.com/read/38036506/the-poxvirus-f17-protein-counteracts-mitochondrially-orchestrated-antiviral-responses
#8
JOURNAL ARTICLE
Nathan Meade, Helen K Toreev, Ram P Chakrabarty, Charles R Hesser, Chorong Park, Navdeep S Chandel, Derek Walsh
Poxviruses are unusual DNA viruses that replicate in the cytoplasm. To do so, they encode approximately 100 immunomodulatory proteins that counteract cytosolic nucleic acid sensors such as cGAMP synthase (cGAS) along with several other antiviral response pathways. Yet most of these immunomodulators are expressed very early in infection while many are variable host range determinants, and significant gaps remain in our understanding of poxvirus sensing and evasion strategies. Here, we show that after infection is established, subsequent progression of the viral lifecycle is sensed through specific changes to mitochondria that coordinate distinct aspects of the antiviral response...
November 30, 2023: Nature Communications
https://read.qxmd.com/read/37873349/post-ischemic-inactivation-of-hif-prolyl-hydroxylases-in-endothelium-promotes-maladaptive-kidney-repair-by-inducing-glycolysis
#9
Ratnakar Tiwari, Rajni Sharma, Ganeshkumar Rajendran, Gabriella S Borkowski, Si Young An, Michael Schonfeld, James O'Sullivan, Matthew J Schipma, Yalu Zhou, Guillaume Courbon, Valentin David, Susan E Quaggin, Edward Thorp, Navdeep S Chandel, Pinelopi P Kapitsinou
Ischemic acute kidney injury (AKI) is common in hospitalized patients and increases the risk for chronic kidney disease (CKD). Impaired endothelial cell (EC) functions are thought to contribute in AKI to CKD transition, but the underlying mechanisms remain unclear. Here, we identify a critical role for endothelial oxygen sensing prolyl hydroxylase domain (PHD) enzymes 1-3 in regulating post-ischemic kidney repair. In renal endothelium, we observed compartment-specific differences in the expression of the three PHD isoforms in both mice and humans...
October 3, 2023: bioRxiv
https://read.qxmd.com/read/37824329/apoe-enhances-mitochondrial-metabolism-via-microrna-142a-146a-regulated-circuits-that-suppress-hematopoiesis-and-inflammation-in-hyperlipidemia
#10
JOURNAL ARTICLE
Tuan Anh Phu, Ngan K Vu, Martin Ng, Alex S Gao, Joshua S Stoolman, Navdeep S Chandel, Robert L Raffai
Apolipoprotein E (ApoE) is recognized for its pleiotropic properties that suppress inflammation. We report that ApoE serves as a metabolic rheostat that regulates microRNA control of glycolytic and mitochondrial activity in myeloid cells and hematopoietic stem and progenitor cells (HSPCs). ApoE expression in myeloid cells increases microRNA-146a, which reduces nuclear factor κB (NF-κB)-driven GLUT1 expression and glycolytic activity. In contrast, ApoE expression reduces microRNA-142a, which increases carnitine palmitoyltransferase 1a (CPT1A) expression, fatty acid oxidation, and oxidative phosphorylation...
October 11, 2023: Cell Reports
https://read.qxmd.com/read/37738954/challenges-and-opportunities-in-targeting-metabolism
#11
JOURNAL ARTICLE
Kivanç Birsoy, Navdeep S Chandel, Sarah-Maria Fendt, Douglas R Green, Xiaoling Li, Deborah M Muoio
Over the past decade or two, targeting metabolism has been effective in the treatment of many diseases and disorders, particularly cancer. In a metabolism focus issue in Cell Chemical Biology, this Voices piece asks researchers from a range of backgrounds: what are some major challenges and opportunities facing the field in the coming years?
September 21, 2023: Cell Chemical Biology
https://read.qxmd.com/read/37558881/mitochondrial-integrated-stress-response-controls-lung-epithelial-cell-fate
#12
JOURNAL ARTICLE
SeungHye Han, Minho Lee, Youngjin Shin, Regina Giovanni, Ram P Chakrabarty, Mariana M Herrerias, Laura A Dada, Annette S Flozak, Paul A Reyfman, Basil Khuder, Colleen R Reczek, Lin Gao, José Lopéz-Barneo, Cara J Gottardi, G R Scott Budinger, Navdeep S Chandel
Alveolar epithelial type 1 (AT1) cells are necessary to transfer oxygen and carbon dioxide between the blood and air. Alveolar epithelial type 2 (AT2) cells serve as a partially committed stem cell population, producing AT1 cells during postnatal alveolar development and repair after influenza A and SARS-CoV-2 pneumonia1-6 . Little is known about the metabolic regulation of the fate of lung epithelial cells. Here we report that deleting the mitochondrial electron transport chain complex I subunit Ndufs2 in lung epithelial cells during mouse gestation led to death during postnatal alveolar development...
August 2023: Nature
https://read.qxmd.com/read/37479688/mof-mediated-histone-h4-lysine-16-acetylation-governs-mitochondrial-and-ciliary-functions-by-controlling-gene-promoters
#13
JOURNAL ARTICLE
Dongmei Wang, Haimin Li, Navdeep S Chandel, Yali Dou, Rui Yi
Histone H4 lysine 16 acetylation (H4K16ac), governed by the histone acetyltransferase MOF, orchestrates gene expression regulation and chromatin interaction. However, the roles of MOF and H4K16ac in controlling cellular function and regulating mammalian tissue development remain unclear. Here we show that conditional deletion of Mof in the skin, but not Kansl1, causes severe defects in the self-renewal of basal epithelial progenitors, epidermal differentiation, and hair follicle growth, resulting in barrier defects and perinatal lethality...
July 21, 2023: Nature Communications
https://read.qxmd.com/read/37452018/lactate-dependent-transcriptional-regulation-controls-mammalian-eye-morphogenesis
#14
JOURNAL ARTICLE
Nozomu Takata, Jason M Miska, Marc A Morgan, Priyam Patel, Leah K Billingham, Neha Joshi, Matthew J Schipma, Zachary J Dumar, Nikita R Joshi, Alexander V Misharin, Ryan B Embry, Luciano Fiore, Peng Gao, Lauren P Diebold, Gregory S McElroy, Ali Shilatifard, Navdeep S Chandel, Guillermo Oliver
Mammalian retinal metabolism favors aerobic glycolysis. However, the role of glycolytic metabolism in retinal morphogenesis remains unknown. We report that aerobic glycolysis is necessary for the early stages of retinal development. Taking advantage of an unbiased approach that combines the use of eye organoids and single-cell RNA sequencing, we identify specific glucose transporters and glycolytic genes in retinal progenitors. Next, we determine that the optic vesicle territory of mouse embryos displays elevated levels of glycolytic activity...
July 14, 2023: Nature Communications
https://read.qxmd.com/read/37399212/yeast-ndi1-reconfigures-neuronal-metabolism-and-prevents-the-unfolded-protein-response-in-mitochondrial-complex-i-deficiency
#15
JOURNAL ARTICLE
Lucy Granat, Debbra Y Knorr, Daniel C Ranson, Emma L Hamer, Ram Prosad Chakrabarty, Francesca Mattedi, Laura Fort-Aznar, Frank Hirth, Sean T Sweeney, Alessio Vagnoni, Navdeep S Chandel, Joseph M Bateman
Mutations in subunits of the mitochondrial NADH dehydrogenase cause mitochondrial complex I deficiency, a group of severe neurological diseases that can result in death in infancy. The pathogenesis of complex I deficiency remain poorly understood, and as a result there are currently no available treatments. To better understand the underlying mechanisms, we modelled complex I deficiency in Drosophila using knockdown of the mitochondrial complex I subunit ND-75 (NDUFS1) specifically in neurons. Neuronal complex I deficiency causes locomotor defects, seizures and reduced lifespan...
July 3, 2023: PLoS Genetics
https://read.qxmd.com/read/37252797/therapeutic-targeting-of-metabolic-vulnerabilities-in-cancers-with-mll3-4-compass-epigenetic-regulator-mutations
#16
JOURNAL ARTICLE
Zibo Zhao, Kaixiang Cao, Jun Watanabe, Cassandra N Philips, Jacob M Zeidner, Yukitomo Ishi, Qixuan Wang, Sarah R Gold, Katherine Junkins, Elizabeth T Bartom, Feng Yue, Navdeep S Chandel, Rintaro Hashizume, Issam Ben-Sahra, Ali Shilatifard
Epigenetic status-altering mutations in chromatin-modifying enzymes are a feature of human diseases, including many cancers. However, the functional outcomes and cellular dependencies arising from these mutations remain unresolved. In this study, we investigated cellular dependencies, or vulnerabilities, that arise when enhancer function is compromised by loss of the frequently mutated COMPASS family members MLL3 and MLL4. CRISPR dropout screens in MLL3/4-depleted mouse embryonic stem cells (mESCs) revealed synthetic lethality upon suppression of purine and pyrimidine nucleotide synthesis pathways...
July 3, 2023: Journal of Clinical Investigation
https://read.qxmd.com/read/37118543/aging-is-associated-with-a-systemic-length-associated-transcriptome-imbalance
#17
JOURNAL ARTICLE
Thomas Stoeger, Rogan A Grant, Alexandra C McQuattie-Pimentel, Kishore R Anekalla, Sophia S Liu, Heliodoro Tejedor-Navarro, Benjamin D Singer, Hiam Abdala-Valencia, Michael Schwake, Marie-Pier Tetreault, Harris Perlman, William E Balch, Navdeep S Chandel, Karen M Ridge, Jacob I Sznajder, Richard I Morimoto, Alexander V Misharin, G R Scott Budinger, Luis A Nunes Amaral
Aging is among the most important risk factors for morbidity and mortality. To contribute toward a molecular understanding of aging, we analyzed age-resolved transcriptomic data from multiple studies. Here, we show that transcript length alone explains most transcriptional changes observed with aging in mice and humans. We present three lines of evidence supporting the biological importance of the uncovered transcriptome imbalance. First, in vertebrates the length association primarily displays a lower relative abundance of long transcripts in aging...
December 2022: Nature aging
https://read.qxmd.com/read/37068235/octopamine-metabolically-reprograms-astrocytes-to-confer-neuroprotection-against-%C3%AE-synuclein
#18
JOURNAL ARTICLE
Andrew Shum, Sofia Zaichick, Gregory S McElroy, Karis D'Alessandro, Milad J Alasady, Michaela Novakovic, Wesley Peng, Ekaterina A Grebenik, Daayun Chung, Margaret E Flanagan, Roger Smith, Alejandro Morales, Laetitia Stumpf, Kaitlyn McGrath, Dimitri Krainc, Marc L Mendillo, Murali Prakriya, Navdeep S Chandel, Gabriela Caraveo
Octopamine is a well-established invertebrate neurotransmitter involved in fight or flight responses. In mammals, its function was replaced by epinephrine. Nevertheless, it is present at trace amounts and can modulate the release of monoamine neurotransmitters by a yet unidentified mechanism. Here, through a multidisciplinary approach utilizing in vitro and in vivo models of α-synucleinopathy, we uncovered an unprecedented role for octopamine in driving the conversion from toxic to neuroprotective astrocytes in the cerebral cortex by fostering aerobic glycolysis...
April 25, 2023: Proceedings of the National Academy of Sciences of the United States of America
https://read.qxmd.com/read/36931250/snapshot-mitochondrial-signaling
#19
JOURNAL ARTICLE
Taylor A Poor, Navdeep S Chandel
Mitochondria have emerged as signaling organelles with roles beyond their well-established function in generating ATP and metabolites for macromolecule synthesis. Healthy mitochondria integrate various physiologic inputs and communicate signals that control cell function or fate as well as adaptation to stress. Dysregulation of these mitochondrial signaling networks are linked to pathology. Here we outline a few modes of signaling between the mitochondrion and the cytoplasm. To view this SnapShot, open or download the PDF...
March 16, 2023: Molecular Cell
https://read.qxmd.com/read/36890308/mitochondrial-molecule-controls-inflammation
#20
Taylor A Poor, Navdeep S Chandel
No abstract text is available yet for this article.
March 8, 2023: Nature
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