title: Resveratrol induces hepatic mitochondrial biogenesis through the sequential activation of nitric oxide and carbon monoxide production.
abstract: OBJECTIVE
  Nitric oxide (NO) can induce mitochondrial biogenesis in cultured cells, through increased guanosine 3',5'-monophosphate (cGMP), and activation of peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α). We sought to determine the role of NO, heme oxygenase-1 (HO-1), and its reaction product (carbon monoxide [CO]) in the induction of mitochondrial biogenesis by the natural antioxidant resveratrol.
  
  
  RESULTS
  S-nitroso-N-acetylpenicillamine (SNAP), an NO donor, induced mitochondrial biogenesis in HepG2 hepatoma cells, and in vivo, through stimulation of PGC-1α. NO-induced mitochondrial biogenesis required cGMP, and was mimicked by the cGMP analogue (8-bromoguanosine 3',5'-cyclic monophosphate [8-Br-cGMP]). Activation of mitochondrial biogenesis by SNAP required HO-1, as it could be reversed by genetic interference of HO-1; and by treatment with the HO inhibitor tin-protoporphyrin-IX (SnPP) in vitro and in vivo. Cobalt protoporphyrin (CoPP)-IX, an HO-1 inducing agent, stimulated mitochondrial biogenesis in HepG2 cells, which could be reversed by the CO scavenger hemoglobin. Application of CO, using the CO-releasing molecule-3 (CORM-3), stimulated mitochondrial biogenesis in HepG2 cells, in a cGMP-dependent manner. Both CoPP and CORM-3-induced mitochondrial biogenesis required NF-E2-related factor-2 (Nrf2) activation and phosphorylation of Akt. The natural antioxidant resveratrol induced mitochondrial biogenesis in HepG2 cells, in a manner dependent on NO biosynthesis, cGMP synthesis, Nrf2-dependent HO-1 activation, and endogenous CO production. Furthermore, resveratrol preserved mitochondrial biogenesis during lipopolysaccharides-induced hepatic inflammation in vivo.
  
  
  CONCLUSIONS
  The complex interplay between endogenous NO and CO production may underlie the mechanism by which natural antioxidants induce mitochondrial biogenesis. Strategies aimed at improving mitochondrial biogenesis may be used as therapeutics for the treatment of diseases involving mitochondrial dysfunction.
authors.affiliation: 1 School of Biological Sciences, University of Ulsan , Ulsan, Korea.
authors.forename: Seul-Ki
authors.initials: SK
authors.lastname: Kim
authors.forename: Yeonsoo
authors.initials: Y
authors.lastname: Joe
authors.forename: Min
authors.initials: M
authors.lastname: Zheng
authors.forename: Hyo Jeong
authors.initials: HJ
authors.lastname: Kim
authors.forename: Jae-Kyoung
authors.initials: JK
authors.lastname: Yu
authors.forename: Gyeong Jae
authors.initials: GJ
authors.lastname: Cho
authors.forename: Ki Churl
authors.initials: KC
authors.lastname: Chang
authors.forename: Hyoung Kyu
authors.initials: HK
authors.lastname: Kim
authors.forename: Jin
authors.initials: J
authors.lastname: Han
authors.forename: Stefan W
authors.initials: SW
authors.lastname: Ryter
authors.forename: Hun Taeg
authors.initials: HT
authors.lastname: Chung
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000494:pharmacology*; D002248:Carbon Monoxide / Q000378:metabolism*; D004195:Disease Models, Animal; D056945:Hep G2 Cells; D006801:Humans; D007274:Injections, Intraperitoneal; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis*; D000077185:Resveratrol; D018805:Sepsis / Q000188:drug therapy / Q000378:metabolism; D013267:Stilbenes / Q000008:administration & dosage / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D000975:Antioxidants; D008070:Lipopolysaccharides; D013267:Stilbenes; D009569:Nitric Oxide; D002248:Carbon Monoxide; D000077185:Resveratrol
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