Endotoxin-stimulated nitric oxide production inhibits expression of cytochrome c oxidase in ANA-1 murine macrophages.
In endotoxin (LPS)-mediated states of sepsis, inducible NO synthase expression and NO production are associated with molecular regulatory functions that determine the host inflammatory response. NO inhibits cellular respiration and mitochondrial electron transport by inhibition of cytochrome c oxidase (CcO) activity. CcO is the terminal complex of the mitochondrial respiratory chain, responsible for 90% of cellular oxygen consumption and essential for cellular energy production. Subunit 1 (CcO I) is considered to be the most critical of the 13 CcO component subunits. In this regard little is known of the effect of NO on the transcriptional program for CcO expression. In ANA-1 murine macrophages, LPS-mediated NO synthesis decreases CcO enzyme activity, CcO I protein expression, and CcO I steady mRNA levels. Mitochondrial run-on analysis demonstrates unaltered CcO I mitochondrial gene transcription. Half-life analysis indicates that CcO I mRNA stability is significantly decreased in the presence of LPS-mediated NO synthesis. In this study using LPS-stimulated ANA-1 murine macrophages, we demonstrate that expression of the mitochondrial gene product, CcO I, is significantly decreased as the result of a unique and previously uncharacterized, NO-dependent post-transcriptional regulatory mechanism.
Wei
Junping
J
Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA.
Guo
Hongtao
H
Kuo
Paul C
PC
D000818:Animals; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D003576:Electron Transport Complex IV / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D020868:Gene Silencing; D006207:Half-Life; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology; D051379:Mice; D024101:Mitochondrial Proteins / Q000096:biosynthesis; D009569:Nitric Oxide / Q000096:biosynthesis*; D012313:RNA / Q000096:biosynthesis; D020871:RNA Stability; D012333:RNA, Messenger / Q000378:metabolism; D000077278:RNA, Mitochondrial
D008070:Lipopolysaccharides; D024101:Mitochondrial Proteins; D012333:RNA, Messenger; D000077278:RNA, Mitochondrial; D009569:Nitric Oxide; D012313:RNA; D003576:Electron Transport Complex IV