Mitochondrial complex I subunits are decreased in murine nonalcoholic fatty liver disease: implication of peroxynitrite.
We investigate the cause of the low activity of mitochondrial complex I found in ob/ob mice with nonalcoholic fatty liver disease. In mitochondrial proteins from ob/ob mice, we assessed complex I activity, fully assembled complex I, and its subunits, oxygen consumption, gene expression of complex I subunits, and oxidative damage to DNA. In mitochondrial proteins from the liver of ob/ob mice, complex I activity, fully assembly of this complex and complex I subunits were markedly reduced. Likewise, gene expression of mitochondrial DNA-encoded subunits was significantly decreased in obese mice, but not nuclear DNA-encoded subunits. Treatment of obese mice with uric acid, anti-TNFalpha antibody or a mimic of manganese superoxide dismutase normalized all these abnormalities. "In vitro" addition of peroxynitrite to mitochondrial proteins from wild-type mice reproduced the abnormalities found in ob/ob mice (decreased complex I activity, the amount of fully assembled complex I, and its subunits, and mitochondrial oxygen consumption). Low activity of complex I found in ob/ob mice can be ascribed to a reduced amount of fully assembled complex, which may be attributed to degradation and reduced synthesis of its subunits by peroxynitrite. Exposure of mitochondrial proteins from normal mice to peroxynitrite reproduced the proteomic abnormalities present in ob/ob mice.
García-Ruiz
Inmaculada
I
Research Center, Laboratory of Gastroenterology and Hepatology, Hospital Universitario 12 de Octubre, 28041 Madrid, Spain.
Fernández-Moreira
Daniel
D
Solís-Muñoz
Pablo
P
Rodríguez-Juan
Cristina
C
Díaz-Sanjuán
Teresa
T
Muñoz-Yagüe
Teresa
T
Solís-Herruzo
José A
JA
D000818:Animals; D004249:DNA Damage; D004272:DNA, Mitochondrial / Q000378:metabolism; D042967:Electron Transport Complex I / Q000737:chemistry / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D005234:Fatty Liver / Q000378:metabolism* / Q000473:pathology; D020738:Leptin / Q000235:genetics; D008099:Liver / Q000737:chemistry / Q000187:drug effects; D008297:Male; D008665:Metalloporphyrins; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008822:Mice, Transgenic; D051336:Mitochondrial Membranes / Q000378:metabolism; D018384:Oxidative Stress; D030421:Peroxynitrous Acid / Q000494:pharmacology*; D000091402:Prohibitins; D012097:Repressor Proteins / Q000378:metabolism
D004272:DNA, Mitochondrial; D020738:Leptin; D008665:Metalloporphyrins; D000091402:Prohibitins; D012097:Repressor Proteins; C097284:manganese(III)-tetrakis(4-benzoic acid)porphyrin; D030421:Peroxynitrous Acid; D042967:Electron Transport Complex I