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

J Cell Sci. 2016 Jan 1;129(1):51-64. doi: 10.1242/jcs.176701. Epub 2015 Nov 24.


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.

Keywords: Degradation; Mitochondria; Ubiquitin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Acyltransferases / metabolism*
  • Animals
  • Cardiolipins / metabolism
  • Cell Line
  • Epithelium / drug effects
  • Epithelium / metabolism*
  • Gene Silencing / drug effects
  • Histone Deacetylase 2 / metabolism
  • Lipopolysaccharides / pharmacology*
  • Lysine / metabolism
  • Lysosomes / drug effects
  • Lysosomes / metabolism
  • Mice
  • Mitochondria / enzymology*
  • Models, Biological
  • Oxygen / metabolism*
  • Proteolysis / drug effects*
  • SKP Cullin F-Box Protein Ligases / metabolism
  • Ubiquitin / metabolism
  • Ubiquitination / drug effects


  • Cardiolipins
  • Lipopolysaccharides
  • Ubiquitin
  • Acyltransferases
  • lysocardiolipin acyltransferase, mouse
  • SKP Cullin F-Box Protein Ligases
  • Histone Deacetylase 2
  • Lysine
  • Oxygen