Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
Increased mitochondrial arginine metabolism supports bioenergetics in asthma
Weiling Xu, … , Satish C. Kalhan, Serpil C. Erzurum
Weiling Xu, … , Satish C. Kalhan, Serpil C. Erzurum
Published May 23, 2016
Citation Information: J Clin Invest. 2016;126(7):2465-2481. https://doi.org/10.1172/JCI82925.
View: Text | PDF
Research Article Metabolism

Increased mitochondrial arginine metabolism supports bioenergetics in asthma

  • Text
  • PDF
Abstract

High levels of arginine metabolizing enzymes, including inducible nitric oxide synthase (iNOS) and arginase (ARG), are typical in asthmatic airway epithelium; however, little is known about the metabolic effects of enhanced arginine flux in asthma. Here, we demonstrated that increased metabolism sustains arginine availability in asthmatic airway epithelium with consequences for bioenergetics and inflammation. Expression of iNOS, ARG2, arginine synthetic enzymes, and mitochondrial respiratory complexes III and IV was elevated in asthmatic lung samples compared with healthy controls. ARG2 overexpression in a human bronchial epithelial cell line accelerated oxidative bioenergetic pathways and suppressed hypoxia-inducible factors (HIFs) and phosphorylation of the signal transducer for atopic Th2 inflammation STAT6 (pSTAT6), both of which are implicated in asthma etiology. Arg2-deficient mice had lower mitochondrial membrane potential and greater HIF-2α than WT animals. In an allergen-induced asthma model, mice lacking Arg2 had greater Th2 inflammation than WT mice, as indicated by higher levels of pSTAT6, IL-13, IL-17, eotaxin, and eosinophils and more mucus metaplasia. Bone marrow transplants from Arg2-deficient mice did not affect airway inflammation in recipient mice, supporting resident lung cells as the drivers of elevated Th2 inflammation. These data demonstrate that arginine flux preserves cellular respiration and suppresses pathological signaling events that promote inflammation in asthma.

Authors

Weiling Xu, Sudakshina Ghosh, Suzy A.A. Comhair, Kewal Asosingh, Allison J. Janocha, Deloris A. Mavrakis, Carole D. Bennett, Lourdes L. Gruca, Brian B. Graham, Kimberly A. Queisser, Christina C. Kao, Samuel H. Wedes, John M. Petrich, Rubin M. Tuder, Satish C. Kalhan, Serpil C. Erzurum

×

Figure 1

Arginine metabolism and bioenergetics in asthma.

Options: View larger image (or click on image) Download as PowerPoint
Arginine metabolism and bioenergetics in asthma.
(A) The citrulline-NO a...
(A) The citrulline-NO and tricarboxylic acid (TCA) cycles. iNOS converts arginine to citrulline and NO. ARG2 converts arginine to ornithine and urea. Ornithine aminotransferase (OAT) converts ornithine to glutamate, which gives rise to αKG to enter the TCA cycle producing reducing equivalents for electron transport chain (ETC) to generate membrane potential for ATP. Aspartate transaminase (AST) uses glutamate to transaminate TCA cycle intermediate oxaloacetate and produces aspartate. Argininosuccinate synthetase (ASS) uses citrulline and aspartate as substrates to form argininosuccinate, which is cleaved by argininosuccinate lyase (ASL) to form arginine and fumarate, linking arginase and iNOS pathways via the citrulline-NO and TCA cycles. (B) Expression in bronchial epithelial cell lysates by Western blot. Cytokeratin confirms epithelial cells obtained by airway brushing. Replicate samples run on parallel gels are presented. (C) Relative units (means ± SEM) in human bronchial epithelial cells (control n ≥ 4, asthma n ≥ 10); 2-tailed t test except 1-tailed t test for complex III-1 and complex IV-4. (D–G) IHC of ARG2 and ASS in endobronchial biopsies of controls and asthmatics. ARG2 is more prominent in asthmatic bronchial epithelium (F) than control (D). Images representative of multiple sections from 15 asthmatics and 7 controls. Bronchial epithelial cells of asthma (G) show stronger cytoplasmic positivity for ASS than control (E). Images representative of multiple sections from 5 asthmatics and 5 controls. Scale bars: 40 μm. (H–K) Immunogold electron microscopy analyses of ARG2 and ASS in epithelium from endobronchial biopsies. I, higher magnification of H, and K of J. White arrowhead shows gold particles. Images representative of 5 individuals. M, mitochondrion. Scale bars: 250 nm.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts