PMID- 18534980
OWN - NLM
STAT- MEDLINE
DCOM- 20080908
LR  - 20240512
IS  - 0021-9258 (Print)
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Linking)
VI  - 283
IP  - 30
DP  - 2008 Jul 25
TI  - Tumor necrosis factor alpha inhibits oxidative phosphorylation through tyrosine 
      phosphorylation at subunit I of cytochrome c oxidase.
PG  - 21134-44
LID - 10.1074/jbc.M801954200 [doi]
AB  - Mitochondrial oxidative phosphorylation provides most cellular energy. As part of 
      this process, cytochrome c oxidase (CcO) pumps protons across the inner 
      mitochondrial membrane, contributing to the generation of the mitochondrial 
      membrane potential, which is used by ATP synthase to produce ATP. During acute 
      inflammation, as in sepsis, aerobic metabolism appears to malfunction and 
      switches to glycolytic energy production. The pro-inflammatory cytokine tumor 
      necrosis factor alpha (TNFalpha) has been shown to play a central role in 
      inflammation. We hypothesized that TNFalpha-triggered cell signaling targets CcO, 
      which is a central enzyme of the aerobic energy metabolism and can be regulated 
      through phosphorylation. Using total bovine and murine hepatocyte homogenates 
      TNFalpha treatment led to an approximately 60% reduction in CcO activity. In 
      contrast, there was no direct effect of TNFalpha on CcO activity using isolated 
      mitochondria and purified CcO, indicating that a TNFalpha-triggered intracellular 
      signaling cascade mediates CcO inhibition. CcO isolated after TNFalpha treatment 
      showed tyrosine phosphorylation on CcO catalytic subunit I and was approximately 
      50 and 70% inhibited at high cytochrome c concentrations in the presence of 
      allosteric activator ADP and inhibitor ATP, respectively. CcO phosphorylation 
      occurs on tyrosine 304 as demonstrated with a phosphoepitope-specific antibody. 
      Furthermore, the mitochondrial membrane potential was decreased in H2.35 cells in 
      response to TNFalpha. Concomitantly, cellular ATP was more than 35 and 64% 
      reduced in murine hepatocytes and H2.35 cells. We postulate that an important 
      contributor in TNFalpha-mediated pathologies, such as sepsis, is energy paucity, 
      which parallels the poor tissue oxygen extraction and utilization found in such 
      patients.
FAU - Samavati, Lobelia
AU  - Samavati L
AD  - Department of Medicine, Division of Pulmonary/Critical Care and Sleep Medicine, 
      Wayne State University School of Medicine, 3990 John R., Detroit, MI 48201, USA. 
      lsamavat@med.wayne.edu
FAU - Lee, Icksoo
AU  - Lee I
FAU - Mathes, Isabella
AU  - Mathes I
FAU - Lottspeich, Friedrich
AU  - Lottspeich F
FAU - Huttemann, Maik
AU  - Huttemann M
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20080605
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 42HK56048U (Tyrosine)
RN  - EC 1.9.3.1 (Electron Transport Complex IV)
RN  - EC 2.7.4.- (ATP Synthetase Complexes)
SB  - IM
MH  - ATP Synthetase Complexes/metabolism
MH  - Animals
MH  - Cattle
MH  - Cells, Cultured
MH  - Electron Transport Complex IV/*metabolism
MH  - Glycolysis
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mitochondria/metabolism
MH  - Models, Biological
MH  - *Oxidative Phosphorylation
MH  - Phosphorylation
MH  - Signal Transduction
MH  - Tumor Necrosis Factor-alpha/*metabolism
MH  - Tyrosine/*chemistry
PMC - PMC3258931
EDAT- 2008/06/07 09:00
MHDA- 2008/09/09 09:00
PMCR- 2009/07/25
CRDT- 2008/06/07 09:00
PHST- 2008/06/07 09:00 [pubmed]
PHST- 2008/09/09 09:00 [medline]
PHST- 2008/06/07 09:00 [entrez]
PHST- 2009/07/25 00:00 [pmc-release]
AID - S0021-9258(19)54736-6 [pii]
AID - 21134 [pii]
AID - 10.1074/jbc.M801954200 [doi]
PST - ppublish
SO  - J Biol Chem. 2008 Jul 25;283(30):21134-44. doi: 10.1074/jbc.M801954200. Epub 2008 
      Jun 5.