Publications by authors named "Navdeep S Chandel"

219 Publications

The Gro3p factor: Restoring NAD+/NADH homeostasis to ameliorate mitochondrial disease.

Cell Metab 2021 Oct;33(10):1905-1907

Department of Medicine, Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. Electronic address:

Leigh syndrome, a mitochondrial disease, can be modeled in mice with a deficiency in mitochondrial complex I that results in a decreased NAD+/NADH ratio. In this issue of Cell Metabolism, Liu et al. (2021) identify glycerol-3-phosphate (Gro3P) biosynthesis as a method for regenerating cytosolic NAD+ to ameliorate pathology in this mitochondrial disease model.
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http://dx.doi.org/10.1016/j.cmet.2021.09.006DOI Listing
October 2021

Metabolism of Proliferating Cells.

Cold Spring Harb Perspect Biol 2021 10 1;13(10). Epub 2021 Oct 1.

Northwestern University, Feinberg School of Medicine, Chicago, Illinois 60611, USA.

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http://dx.doi.org/10.1101/cshperspect.a040618DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8485748PMC
October 2021

Lipid Metabolism.

Cold Spring Harb Perspect Biol 2021 09 1;13(9). Epub 2021 Sep 1.

Northwestern University, Feinberg School of Medicine, Chicago, Illinois 60611, USA.

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http://dx.doi.org/10.1101/cshperspect.a040576DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8411952PMC
September 2021

Metabolic decisions in development and disease-a Keystone Symposia report.

Ann N Y Acad Sci 2021 Aug 19. Epub 2021 Aug 19.

Departments of Biological Chemistry and Molecular & Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, California.

There is an increasing appreciation for the role of metabolism in cell signaling and cell decision making. Precise metabolic control is essential in development, as evident by the disorders caused by mutations in metabolic enzymes. The metabolic profile of cells is often cell-type specific, changing as cells differentiate or during tumorigenesis. Recent evidence has shown that changes in metabolism are not merely a consequence of changes in cell state but that metabolites can serve to promote and/or inhibit these changes. Metabolites can link metabolic pathways with cell signaling pathways via several mechanisms, for example, by serving as substrates for protein post-translational modifications, by affecting enzyme activity via allosteric mechanisms, or by altering epigenetic markers. Unraveling the complex interactions governing metabolism, gene expression, and protein activity that ultimately govern a cell's fate will require new tools and interactions across disciplines. On March 24 and 25, 2021, experts in cell metabolism, developmental biology, and human disease met virtually for the Keystone eSymposium, "Metabolic Decisions in Development and Disease." The discussions explored how metabolites impact cellular and developmental decisions in a diverse range of model systems used to investigate normal development, developmental disorders, dietary effects, and cancer-mediated changes in metabolism.
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http://dx.doi.org/10.1111/nyas.14678DOI Listing
August 2021

Hypoxic preconditioning protects against ischemic kidney injury through the IDO1/kynurenine pathway.

Cell Rep 2021 Aug;36(7):109547

Feinberg Cardiovascular and Renal Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; Department of Medicine and Robert H. Lurie Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; Division of Nephrology & Hypertension, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. Electronic address:

Prolonged cellular hypoxia leads to energetic failure and death. However, sublethal hypoxia can trigger an adaptive response called hypoxic preconditioning. While prolyl-hydroxylase (PHD) enzymes and hypoxia-inducible factors (HIFs) have been identified as key elements of oxygen-sensing machinery, the mechanisms by which hypoxic preconditioning protects against insults remain unclear. Here, we perform serum metabolomic profiling to assess alterations induced by two potent cytoprotective approaches, hypoxic preconditioning and pharmacologic PHD inhibition. We discover that both approaches increase serum kynurenine levels and enhance kynurenine biotransformation, leading to preservation of NAD in the post-ischemic kidney. Furthermore, we show that indoleamine 2,3-dioxygenase 1 (Ido1) deficiency abolishes the systemic increase of kynurenine and the subsequent renoprotection generated by hypoxic preconditioning and PHD inhibition. Importantly, exogenous administration of kynurenine restores the hypoxic preconditioning in the context of Ido1 deficiency. Collectively, our findings demonstrate a critical role of the IDO1-kynurenine axis in mediating hypoxic preconditioning.
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http://dx.doi.org/10.1016/j.celrep.2021.109547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8487442PMC
August 2021

Basics of Metabolic Reactions.

Cold Spring Harb Perspect Biol 2021 08 2;13(8). Epub 2021 Aug 2.

Northwestern University, Feinberg School of Medicine, Chicago, Illinois 60611, USA.

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http://dx.doi.org/10.1101/cshperspect.a040527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8327831PMC
August 2021

Cancer metabolism: looking forward.

Nat Rev Cancer 2021 10 16;21(10):669-680. Epub 2021 Jul 16.

Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

Tumour initiation and progression requires the metabolic reprogramming of cancer cells. Cancer cells autonomously alter their flux through various metabolic pathways in order to meet the increased bioenergetic and biosynthetic demand as well as mitigate oxidative stress required for cancer cell proliferation and survival. Cancer driver mutations coupled with environmental nutrient availability control flux through these metabolic pathways. Metabolites, when aberrantly accumulated, can also promote tumorigenesis. The development and application of new technologies over the last few decades has not only revealed the heterogeneity and plasticity of tumours but also allowed us to uncover new metabolic pathways involved in supporting tumour growth. The tumour microenvironment (TME), which can be depleted of certain nutrients, forces cancer cells to adapt by inducing nutrient scavenging mechanisms to sustain cancer cell proliferation. There is growing appreciation that the metabolism of cell types other than cancer cells within the TME, including endothelial cells, fibroblasts and immune cells, can modulate tumour progression. Because metastases are a major cause of death of patients with cancer, efforts are underway to understand how metabolism is harnessed by metastatic cells. Additionally, there is a new interest in exploiting cancer genetic analysis for patient stratification and/or dietary interventions in combination with therapies that target metabolism. In this Perspective, we highlight these main themes that are currently under investigation in the context of in vivo tumour metabolism, specifically emphasizing questions that remain unanswered.
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http://dx.doi.org/10.1038/s41568-021-00378-6DOI Listing
October 2021

Nucleotide Metabolism.

Cold Spring Harb Perspect Biol 2021 07 1;13(7). Epub 2021 Jul 1.

Northwestern University, Feinberg School of Medicine, Chicago, Illinois 60611, USA.

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http://dx.doi.org/10.1101/cshperspect.a040592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8247561PMC
July 2021

NADPH-The Forgotten Reducing Equivalent.

Cold Spring Harb Perspect Biol 2021 06 1;13(6). Epub 2021 Jun 1.

Northwestern University, Feinberg School of Medicine, Chicago, Illinois 60611, USA.

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http://dx.doi.org/10.1101/cshperspect.a040550DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168431PMC
June 2021

Glycolysis.

Cold Spring Harb Perspect Biol 2021 05 3;13(5). Epub 2021 May 3.

Northwestern University, Feinberg School of Medicine, Chicago, Illinois 60611, USA.

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http://dx.doi.org/10.1101/cshperspect.a040535DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8091952PMC
May 2021

Mitochondrial respiration controls the Prox1-Vegfr3 feedback loop during lymphatic endothelial cell fate specification and maintenance.

Sci Adv 2021 Apr 30;7(18). Epub 2021 Apr 30.

Center for Vascular and Developmental Biology, Feinberg Cardiovascular and Renal Research Institute, Northwestern University, Chicago, IL, USA.

Recent findings indicate that mitochondrial respiration regulates blood endothelial cell proliferation; however, its role in differentiating lymphatic endothelial cells (LECs) is unknown. We hypothesized that mitochondria could work as a sensor of LECs' metabolic specific needs by determining their functional requirements according to their differentiation status and local tissue microenvironment. Accordingly, we conditionally deleted the QPC subunit of mitochondrial complex III in differentiating LECs of mouse embryos. Unexpectedly, mutant mice were devoid of a lymphatic vasculature by mid-gestation, a consequence of the specific down-regulation of main LEC fate regulators, particularly Vegfr3, leading to the loss of LEC fate. Mechanistically, this is a result of reduced H3K4me3 and H3K27ac in the genomic locus of key LEC fate controllers (e.g., and ). Our findings indicate that by sensing the LEC differentiation status and microenvironmental metabolic conditions, mitochondrial complex III regulates the critical Prox1-Vegfr3 feedback loop and, therefore, LEC fate specification and maintenance.
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http://dx.doi.org/10.1126/sciadv.abe7359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087398PMC
April 2021

Mitochondrial Metabolism Regulation of T Cell-Mediated Immunity.

Annu Rev Immunol 2021 04;39:395-416

Department of Medicine, Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA; email:

Recent evidence supports the notion that mitochondrial metabolism is necessary for T cell activation, proliferation, and function. Mitochondrial metabolism supports T cell anabolism by providing key metabolites for macromolecule synthesis and generating metabolites for T cell function. In this review, we focus on how mitochondrial metabolism controls conventional and regulatory T cell fates and function.
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http://dx.doi.org/10.1146/annurev-immunol-101819-082015DOI Listing
April 2021

Lessons from Cancer Metabolism for Pulmonary Arterial Hypertension and Fibrosis.

Am J Respir Cell Mol Biol 2021 08;65(2):134-145

Division of Pulmonary and Critical Care, Department of Medicine, and.

Metabolism is essential for a living organism to sustain life. It provides energy to a cell by breaking down compounds (catabolism) and supplies building blocks for the synthesis of macromolecules (anabolism). Signal transduction pathways tightly regulate mammalian cellular metabolism. Simultaneously, metabolism itself serves as a signaling pathway to control many cellular processes, such as proliferation, differentiation, cell death, gene expression, and adaptation to stress. Considerable progress in the metabolism field has come from understanding how cancer cells co-opt metabolic pathways for growth and survival. Recent data also show that several metabolic pathways may participate in the pathogenesis of lung diseases, some of which could be promising therapeutic targets. In this translational review, we will outline the basic metabolic principles learned from the cancer metabolism field as they apply to the pathogenesis of pulmonary arterial hypertension and fibrosis and will place an emphasis on therapeutic potential.
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http://dx.doi.org/10.1165/rcmb.2020-0550TRDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8399574PMC
August 2021

Amino Acid Metabolism.

Cold Spring Harb Perspect Biol 2021 04 1;13(4). Epub 2021 Apr 1.

Northwestern University, Feinberg School of Medicine, Chicago, Illinois 60611, USA.

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http://dx.doi.org/10.1101/cshperspect.a040584DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8015690PMC
April 2021

Mitochondrial metabolism is essential for invariant natural killer T cell development and function.

Proc Natl Acad Sci U S A 2021 03;118(13)

Department of Microbiology and Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611;

Conventional T cell fate and function are determined by coordination between cellular signaling and mitochondrial metabolism. Invariant natural killer T (iNKT) cells are an important subset of "innate-like" T cells that exist in a preactivated effector state, and their dependence on mitochondrial metabolism has not been previously defined genetically or in vivo. Here, we show that mature iNKT cells have reduced mitochondrial respiratory reserve and iNKT cell development was highly sensitive to perturbation of mitochondrial function. Mice with T cell-specific ablation of Rieske iron-sulfur protein (RISP; T- ), an essential subunit of mitochondrial complex III, had a dramatic reduction of iNKT cells in the thymus and periphery, but no significant perturbation on the development of conventional T cells. The impaired development observed in T- mice stems from a cell-autonomous defect in iNKT cells, resulting in a differentiation block at the early stages of iNKT cell development. Residual iNKT cells in T- mice displayed increased apoptosis but retained the ability to proliferate in vivo, suggesting that their bioenergetic and biosynthetic demands were not compromised. However, they exhibited reduced expression of activation markers, decreased T cell receptor (TCR) signaling and impaired responses to TCR and interleukin-15 stimulation. Furthermore, knocking down RISP in mature iNKT cells diminished their cytokine production, correlating with reduced NFATc2 activity. Collectively, our data provide evidence for a critical role of mitochondrial metabolism in iNKT cell development and activation outside of its traditional role in supporting cellular bioenergetic demands.
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http://dx.doi.org/10.1073/pnas.2021385118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020658PMC
March 2021

SGK1 signaling promotes glucose metabolism and survival in extracellular matrix detached cells.

Cell Rep 2021 03;34(11):108821

Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556, USA. Electronic address:

Loss of integrin-mediated attachment to extracellular matrix (ECM) proteins can trigger a variety of cellular changes that affect cell viability. Foremost among these is the activation of anoikis, caspase-mediated cell death induced by ECM detachment. In addition, loss of ECM attachment causes profound alterations in cellular metabolism, which can lead to anoikis-independent cell death. Here, we describe a surprising role for serum and glucocorticoid kinase-1 (SGK1) in the promotion of energy production when cells are detached. Our data demonstrate that SGK1 activation is necessary and sufficient for ATP generation during ECM detachment and anchorage-independent growth. More specifically, SGK1 promotes a substantial elevation in glucose uptake because of elevated GLUT1 transcription. In addition, carbon flux into the pentose phosphate pathway (PPP) is necessary to accommodate elevated glucose uptake and PPP-mediated glyceraldehyde-3-phosphate (G3P) is necessary for ATP production. Thus, our data show SGK1 as master regulator of glucose metabolism and cell survival during ECM-detached conditions.
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http://dx.doi.org/10.1016/j.celrep.2021.108821DOI Listing
March 2021

Mitochondria as Signaling Organelles Control Mammalian Stem Cell Fate.

Cell Stem Cell 2021 03;28(3):394-408

Department of Medicine, Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. Electronic address:

Recent evidence supports the notion that mitochondrial metabolism is necessary for the determination of stem cell fate. Historically, mitochondrial metabolism is linked to the production of ATP and tricarboxylic acid (TCA) cycle metabolites to support stem cell survival and growth, respectively. However, it is now clear that beyond these canonical roles, mitochondria as signaling organelles dictate stem cell fate and function. In this review, we focus on key conceptual ideas on how mitochondria control mammalian stem cell fate and function through reactive oxygen species (ROS) generation, TCA cycle metabolite production, NAD/NADH ratio regulation, pyruvate metabolism, and mitochondrial dynamics.
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http://dx.doi.org/10.1016/j.stem.2021.02.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7944920PMC
March 2021

Mitochondria.

Cold Spring Harb Perspect Biol 2021 03 1;13(3). Epub 2021 Mar 1.

Northwestern University, Feinberg School of Medicine, Chicago, Illinois 60611, USA.

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http://dx.doi.org/10.1101/cshperspect.a040543DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919390PMC
March 2021

Polyamines drive myeloid cell survival by buffering intracellular pH to promote immunosuppression in glioblastoma.

Sci Adv 2021 Feb 17;7(8). Epub 2021 Feb 17.

Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, 676 North St. Clair Street, Suite 2210, Chicago, IL 60611, USA.

Glioblastoma is characterized by the robust infiltration of immunosuppressive tumor-associated myeloid cells (TAMCs). It is not fully understood how TAMCs survive in the acidic tumor microenvironment to cause immunosuppression in glioblastoma. Metabolic and RNA-seq analysis of TAMCs revealed that the arginine-ornithine-polyamine axis is up-regulated in glioblastoma TAMCs but not in tumor-infiltrating CD8 T cells. Active de novo synthesis of highly basic polyamines within TAMCs efficiently buffered low intracellular pH to support the survival of these immunosuppressive cells in the harsh acidic environment of solid tumors. Administration of difluoromethylornithine (DFMO), a clinically approved inhibitor of polyamine generation, enhanced animal survival in immunocompetent mice by causing a tumor-specific reduction of polyamines and decreased intracellular pH in TAMCs. DFMO combination with immunotherapy or radiotherapy further enhanced animal survival. These findings indicate that polyamines are used by glioblastoma TAMCs to maintain normal intracellular pH and cell survival and thus promote immunosuppression during tumor evolution.
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http://dx.doi.org/10.1126/sciadv.abc8929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7888943PMC
February 2021

The lung microenvironment shapes a dysfunctional response of alveolar macrophages in aging.

J Clin Invest 2021 02;131(4)

Department of Medicine, Division of Pulmonary and Critical Care Medicine, Northwestern University, Chicago, Illinois, USA.

Alveolar macrophages orchestrate the response to viral infections. Age-related changes in these cells may underlie the differential severity of pneumonia in older patients. We performed an integrated analysis of single-cell RNA-Seq data that revealed homogenous age-related changes in the alveolar macrophage transcriptome in humans and mice. Using genetic lineage tracing with sequential injury, heterochronic adoptive transfer, and parabiosis, we found that the lung microenvironment drove an age-related resistance of alveolar macrophages to proliferation that persisted during influenza A viral infection. Ligand-receptor pair analysis localized these changes to the extracellular matrix, where hyaluronan was increased in aged animals and altered the proliferative response of bone marrow-derived macrophages to granulocyte macrophage colony-stimulating factor (GM-CSF). Our findings suggest that strategies targeting the aging lung microenvironment will be necessary to restore alveolar macrophage function in aging.
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http://dx.doi.org/10.1172/JCI140299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919859PMC
February 2021

LKB1/ Is a Tumor Suppressor in the Progression of Myeloproliferative Neoplasms.

Cancer Discov 2021 Jun 12;11(6):1398-1410. Epub 2021 Feb 12.

Northwestern University, Chicago, Illinois.

The myeloproliferative neoplasms (MPN) frequently progress to blast phase disease, an aggressive form of acute myeloid leukemia. To identify genes that suppress disease progression, we performed a focused CRISPR/Cas9 screen and discovered that depletion of LKB1/ led to enhanced self-renewal of murine MPN cells. Deletion of in a mouse MPN model caused rapid lethality with enhanced fibrosis, osteosclerosis, and an accumulation of immature cells in the bone marrow, as well as enhanced engraftment of primary human MPN cells . LKB1 loss was associated with increased mitochondrial reactive oxygen species and stabilization of HIF1α, and downregulation of LKB1 and increased levels of HIF1α were observed in human blast phase MPN specimens. Of note, we observed strong concordance of pathways that were enriched in murine MPN cells with LKB1 loss with those enriched in blast phase MPN patient specimens, supporting the conclusion that is a tumor suppressor in the MPNs. SIGNIFICANCE: Progression of the myeloproliferative neoplasms to acute myeloid leukemia occurs in a substantial number of cases, but the genetic basis has been unclear. We discovered that loss of LKB1/ leads to stabilization of HIF1a and promotes disease progression. This observation provides a potential therapeutic avenue for targeting progression..
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http://dx.doi.org/10.1158/2159-8290.CD-20-1353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8178182PMC
June 2021

Elevated CO Levels Delay Skeletal Muscle Repair by Increasing Fatty Acid Oxidation.

Front Physiol 2020 21;11:630910. Epub 2021 Jan 21.

Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States.

Muscle dysfunction often occurs in patients with chronic obstructive pulmonary diseases (COPD) and affects ventilatory and non-ventilatory skeletal muscles. We have previously reported that hypercapnia (elevated CO levels) causes muscle atrophy through the activation of the AMPKα2-FoxO3a-MuRF1 pathway. In the present study, we investigated the effect of normoxic hypercapnia on skeletal muscle regeneration. We found that mouse C2C12 myoblasts exposed to elevated CO levels had decreased fusion index compared to myoblasts exposed to normal CO. Metabolic analyses of C2C12 myoblasts exposed to high CO showed increased oxidative phosphorylation due to increased fatty acid oxidation. We utilized the cardiotoxin-induced muscle injury model in mice exposed to normoxia and 10% CO for 21 days and observed that muscle regeneration was delayed. High CO-delayed differentiation in both mouse C2C12 myoblasts and skeletal muscle after injury and was restored to control levels when cells or mice were treated with a carnitine palmitoyltransfearse-1 (CPT1) inhibitor. Taken together, our data suggest that hypercapnia leads to changes in the metabolic activity of skeletal muscle cells, which results in impaired muscle regeneration and recovery after injury.
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http://dx.doi.org/10.3389/fphys.2020.630910DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859333PMC
January 2021

Signaling and Metabolism.

Cold Spring Harb Perspect Biol 2021 02 1;13(2). Epub 2021 Feb 1.

Northwestern University, Feinberg School of Medicine, Chicago, Illinois 60611, USA.

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http://dx.doi.org/10.1101/cshperspect.a040600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7849339PMC
February 2021

Treating mitochondrial diseases with antibiotics.

Nat Metab 2021 Jan;3(1):5-6

Department of Medicine, Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

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http://dx.doi.org/10.1038/s42255-020-00336-wDOI Listing
January 2021

Targeting Bacteria within Us to Diminish Infection and Autoimmunity.

Immunity 2021 01;54(1):1-3

Department of Medicine, Biochemistry, and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. Electronic address:

Antibiotics improve clinical outcomes independent of their antibacterial effects. In this issue of Immunity, Almeida et al. and Colaço et al. demonstrate that antibiotic impairment of mitochondrial ribosomes modulates both T-cell-dependent inflammation and host tolerance to infection.
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http://dx.doi.org/10.1016/j.immuni.2020.12.006DOI Listing
January 2021

Carbohydrate Metabolism.

Cold Spring Harb Perspect Biol 2021 01 4;13(1). Epub 2021 Jan 4.

Northwestern University, Feinberg School of Medicine, Chicago, Illinois 60611, USA.

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http://dx.doi.org/10.1101/cshperspect.a040568DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7778149PMC
January 2021

Kidney epithelial targeted mitochondrial transcription factor A deficiency results in progressive mitochondrial depletion associated with severe cystic disease.

Kidney Int 2021 03 4;99(3):657-670. Epub 2020 Nov 4.

Department of Medicine, Vanderbilt University Medical Center and Vanderbilt University School of Medicine, Nashville, Tennessee, USA; The Vanderbilt O'Brien Kidney Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA; Medical and Research Services, Department of Veterans Affairs Hospital, Tennessee Valley Healthcare System, Nashville, Tennessee, USA; Department of Molecular Physiology and Biophysics, and Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA. Electronic address:

Abnormal mitochondrial function is a well-recognized feature of acute and chronic kidney diseases. To gain insight into the role of mitochondria in kidney homeostasis and pathogenesis, we targeted mitochondrial transcription factor A (TFAM), a protein required for mitochondrial DNA replication and transcription that plays a critical part in the maintenance of mitochondrial mass and function. To examine the consequences of disrupted mitochondrial function in kidney epithelial cells, we inactivated TFAM in sine oculis-related homeobox 2-expressing kidney progenitor cells. TFAM deficiency resulted in significantly decreased mitochondrial gene expression, mitochondrial depletion, inhibition of nephron maturation and the development of severe postnatal cystic disease, which resulted in premature death. This was associated with abnormal mitochondrial morphology, a reduction in oxygen consumption and increased glycolytic flux. Furthermore, we found that TFAM expression was reduced in murine and human polycystic kidneys, which was accompanied by mitochondrial depletion. Thus, our data suggest that dysregulation of TFAM expression and mitochondrial depletion are molecular features of kidney cystic disease that may contribute to its pathogenesis.
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http://dx.doi.org/10.1016/j.kint.2020.10.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8209657PMC
March 2021

Mitochondrial Dysfunction in Fragile-X Syndrome: Plugging the Leak May Save the Ship.

Mol Cell 2020 11;80(3):381-383

Department of Medicine, Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. Electronic address:

Recent work by Licznerski et al. suggests that mutant FMRP linked to Fragile-X syndrome elevates the inner mitochondrial membrane proton leak, leading to increased metabolism and changes in protein synthesis that trigger impaired synaptic maturation and autistic behaviors.
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http://dx.doi.org/10.1016/j.molcel.2020.10.002DOI Listing
November 2020

Metabolic determinants of cellular fitness dependent on mitochondrial reactive oxygen species.

Sci Adv 2020 Nov 4;6(45). Epub 2020 Nov 4.

Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.

Mitochondria-derived reactive oxygen species (mROS) are required for the survival, proliferation, and metastasis of cancer cells. The mechanism by which mitochondrial metabolism regulates mROS levels to support cancer cells is not fully understood. To address this, we conducted a metabolism-focused CRISPR-Cas9 genetic screen and uncovered that loss of genes encoding subunits of mitochondrial complex I was deleterious in the presence of the mitochondria-targeted antioxidant mito-vitamin E (MVE). Genetic or pharmacologic inhibition of mitochondrial complex I in combination with the mitochondria-targeted antioxidants, MVE or MitoTEMPO, induced a robust integrated stress response (ISR) and markedly diminished cell survival and proliferation in vitro. This was not observed following inhibition of mitochondrial complex III. Administration of MitoTEMPO in combination with the mitochondrial complex I inhibitor phenformin decreased the leukemic burden in a mouse model of T cell acute lymphoblastic leukemia. Thus, mitochondrial complex I is a dominant metabolic determinant of mROS-dependent cellular fitness.
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http://dx.doi.org/10.1126/sciadv.abb7272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673681PMC
November 2020

Epithelial cell-specific loss of function of causes a spontaneous COPD-like phenotype and up-regulates expression in mice.

Sci Adv 2020 08 14;6(33):eabb7238. Epub 2020 Aug 14.

Department of Surgery, College of Medicine and University of Illinois Cancer Center, University of Illinois at Chicago, Chicago, IL 60612, USA.

Cigarette smoking, the leading cause of chronic obstructive pulmonary disease (COPD), has been implicated as a risk factor for severe disease in patients infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here we show that mice with lung epithelial cell-specific loss of function of , which we identified as a negative regulator of nuclear factor κB (NF-κB) signaling, spontaneously develop progressive age-related changes resembling COPD. Furthermore, loss of Miz1 up-regulates the expression of , the receptor for SARS-CoV-2. Concomitant partial loss of κ prevented the development of COPD-like phenotype in -deficient mice. Miz1 protein levels are reduced in the lungs from patients with COPD, and in the lungs of mice exposed to chronic cigarette smoke. Our data suggest that Miz1 down-regulation-induced sustained activation of NF-κB-dependent inflammation in the lung epithelium is sufficient to induce progressive lung and airway destruction that recapitulates features of COPD, with implications for COVID-19.
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http://dx.doi.org/10.1126/sciadv.abb7238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7428331PMC
August 2020
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