LPS impairs oxygen utilization in epithelia by triggering degradation of the mitochondrial enzyme Alcat1

Details

• Personal Author:
  Chen BB ; Das S ; Jiang J ; Kagan VE ; Lee JS ; Li J ; Liu Y ; Mallampalli RK ; Manni ML ; Ray A ; Ray P ; Shiva S ; Synan MJ ; Tyurina YY ; Xiong S ; Zhao Y ; Zou C ; Chen BB ; Das S ; Jiang J ; Kagan VE ; Lee JS ; Li J ; Liu Y ; Mallampalli RK ; Manni ML ; Ray A ; Ray P ; Shiva S ; Synan MJ ; Tyurina YY ; Xiong S ; Zhao Y ; Zou C
• Description:
  Cardiolipin (also known as PDL6) is an indispensable lipid required for mitochondrial respiration that is generated through de novo synthesis and remodeling. Here, the cardiolipin remodeling enzyme, acyl-CoA:lysocardiolipin-acyltransferase-1 (Alcat1; SwissProt ID, Q6UWP7) is destabilized in epithelia by lipopolysaccharide (LPS) impairing mitochondrial function. Exposure to LPS selectively decreased levels of carbon 20 (C20)-containing cardiolipin molecular species, whereas the content of C18 or C16 species was not significantly altered, consistent with decreased levels of Alcat1. Alcat1 is a labile protein that is lysosomally degraded by the ubiquitin E3 ligase Skp-Cullin-F-box containing the Fbxo28 subunit (SCF-Fbxo28) that targets Alcat1 for monoubiquitylation at residue K183. Interestingly, K183 is also an acetylation-acceptor site, and acetylation conferred stability to the enzyme. Histone deacetylase 2 (HDAC2) interacted with Alcat1, and expression of a plasmid encoding HDAC2 or treatment of cells with LPS deacetylated and destabilized Alcat1, whereas treatment of cells with a pan-HDAC inhibitor increased Alcat1 levels. Alcat1 degradation was partially abrogated in LPS-treated cells that had been silenced for HDAC2 or treated with MLN4924, an inhibitor of Cullin-RING E3 ubiquitin ligases. Thus, LPS increases HDAC2-mediated Alcat1 deacetylation and facilitates SCF-Fbxo28-mediated disposal of Alcat1, thus impairing mitochondrial integrity. [Description provided by NIOSH]
• Subjects:
  Animals Energy Metabolism Genetics Laboratories Occupational Health Safety
• Keywords:
  Author Keywords: Degradation Biological Effects Biological Function Cell Function Cell Metabolism Drugs Enzymology Genes Health Effects Laboratory Animals Metabolism Mitochondria Pharmacology Proteins Ubiquitin

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• ISSN:
  0021-9533
• Document Type:
  Text
• Funding:
  Grant
• Genre:
  Journal Article ; Journal Article
• Place as Subject:
  OSHA Region 3 ; Pennsylvania
• CIO:
  National Institute for Occupational Safety and Health (NIOSH) ; National Institute for Occupational Safety and Health (NIOSH)
• Topic:
  Workplace Safety & Health ; Workplace Safety & Health
• Location:
  North America ; North America
• Pages in Document:
  51-64
• Volume:
  129
• Issue:
  1
• NIOSHTIC Number:
  nn:20048810
• Citation:
  J Cell Sci 2016 Jan; 129(1):51-64
• Contact Point Address:
  Rama K. Mallampalli, Department of Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, PA 15213
• Email:
  mallampallirk@upmc.edu
• CAS Registry Number:
  Oxygen (CAS RN 7782-44-7) ; Oxygen (CAS RN 7782-44-7)
• Federal Fiscal Year:
  2016
• NORA Priority Area:
  Manufacturing ; Manufacturing
• Performing Organization:
  University of Pittsburgh at Pittsburgh
• Peer Reviewed:
  True
• Start Date:
  20050701
• Source Full Name:
  Journal of Cell Science
• End Date:
  20160630
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:45a62d6d7bba8f3214b703161a339f7c05b47b3cfd7474ae1c9e80709e385f46ae3b3545e71c893f99089d413fb444f1b47f17a19405688215bb619303b447ac
• Download URL:
  https://stacks.cdc.gov/view/cdc/203441/cdc_203441_DS1.pdf
• File Type:
  [PDF - 3.48 MB ]