title: Melatonin improves mitochondrial respiratory chain activity and liver morphology in ob/ob mice.
abstract: In previous studies, we have shown that mitochondrial respiratory chain (MRC) activity is decreased in patients with nonalcoholic steatohepatitis and in ob/ob mice and that peroxynitrite plays a pathogenic role. The present study examined whether melatonin, a peroxynitrite scavenger, prevents: (i) the in vitro effects of peroxynitrite on normal mitochondrial proteins and (ii) the development of nonalcoholic liver disease, MRC dysfunction and proteomic changes found in the mitochondrial complexes from ob/ob mice. We studied MRC activity, assembly of mitochondrial complexes and its subunits in normal mitochondrial proteins exposed to peroxynitrite in the absence and presence of melatonin. The same studies were done in mitochondrial proteins from ob/ob mice untreated and treated with melatonin. Preincubation of mitochondrial proteins from wild-type mice with melatonin prevented 3-tyrosine nitration of these proteins, eliminated the reduction in the MRC activity, the defect in the assembly of mitochondrial complexes and degradation of their subunits induced by peroxynitrite in vitro. Moreover, treatment of ob/ob mice with 10 mg/kg/day melatonin for 12 wk reduced oxidative and nitrosative stress, prevented the loss of MRC activity, protected their complexes and subunits from degradation, and favored assembling of mitochondrial complexes. In addition, this treatment improved fatty liver, decreased hepatic triglyceride concentration and increased apolipoprotein B100 in liver tissue. In conclusion, melatonin prevents the effects of peroxynitrite on mitochondrial proteins in vitro and administration of melatonin to ob/ob mice normalizes liver morphology, mitochondrial dysfunction and assembly of MRC complexes.
authors.affiliation: Research Center, Hospital Universitario 12 de Octubre, Universidad Complutense, School of Medicine, Madrid, Spain.
authors.forename: Pablo
authors.initials: P
authors.lastname: Solís-Muñoz
authors.forename: José A
authors.initials: JA
authors.lastname: Solís-Herruzo
authors.forename: Daniel
authors.initials: D
authors.lastname: Fernández-Moreira
authors.forename: Erica
authors.initials: E
authors.lastname: Gómez-Izquierdo
authors.forename: Inés
authors.initials: I
authors.lastname: García-Consuegra
authors.forename: Teresa
authors.initials: T
authors.lastname: Muñoz-Yagüe
authors.forename: Inmaculada
authors.initials: I
authors.lastname: García Ruiz
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001835:Body Weight / Q000187:drug effects; D045222:Electron Transport Chain Complex Proteins / Q000378:metabolism*; D005234:Fatty Liver / Q000378:metabolism / Q000517:prevention & control; D006651:Histocytochemistry; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000473:pathology; D008297:Male; D008550:Melatonin / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D009566:Nitrates / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D030421:Peroxynitrous Acid / Q000494:pharmacology; D021122:Protein Subunits; D014443:Tyrosine / Q000378:metabolism
chemical_list: D045222:Electron Transport Chain Complex Proteins; D009566:Nitrates; D021122:Protein Subunits; D030421:Peroxynitrous Acid; D014443:Tyrosine; C015566:3-tyrosine; D008550:Melatonin