Peroxiredoxin-6 protects against mitochondrial dysfunction and liver injury during ischemia-reperfusion in mice.
Hepatic ischemia-reperfusion (I/R) injury is an important complication of liver surgery and transplantation. Mitochondrial function is central to this injury. To examine alterations in mitochondrial function during I/R, we assessed the mitochondrial proteome in C57Bl/6 mice. Proteomic analysis of liver mitochondria revealed 234 proteins with significantly altered expression after I/R. From these, 13 proteins with the greatest expression differences were identified. One of these proteins, peroxiredoxin-6 (Prdx6), has never before been described in mitochondria. In hepatocytes from sham-operated mice, Prdx6 expression was found exclusively in the cytoplasm. After ischemia or I/R, Prdx6 expression disappeared from the cytoplasm and appeared in the mitochondria, suggesting mitochondrial trafficking. To explore the functional role of Prdx6 in hepatic I/R injury, wild-type and Prdx6-knockout mice were subjected to I/R injury. Prdx6-knockout mice had significantly more hepatocellular injury compared with wild-type mice. Interestingly, the increased injury in Prdx6-knockout mice occurred despite reduced inflammation and was associated with increased mitochondrial generation of H(2)O(2) and dysfunction. The mitochondrial dysfunction appeared to be related to complex I of the electron transport chain. These data suggest that hepatocyte Prdx6 traffics to the mitochondria during I/R to limit mitochondrial dysfunction as a protective mechanism against hepatocellular injury.
Eismann
Thorsten
T
Department of Surgery, University of Cincinnati, Cincinnati, OH 45267-0558, USA.
Huber
Nadine
N
Shin
Thomas
T
Kuboki
Satoshi
S
Galloway
Elizabeth
E
Wyder
Michael
M
Edwards
Michael J
MJ
Greis
Kenneth D
KD
Shertzer
Howard G
HG
Fisher
Aron B
AB
Lentsch
Alex B
AB
D000818:Animals; D003593:Cytoplasm / Q000201:enzymology; D004195:Disease Models, Animal; D004579:Electron Transport; D042967:Electron Transport Complex I / Q000378:metabolism; D022781:Hepatocytes / Q000201:enzymology; D006861:Hydrogen Peroxide / Q000378:metabolism; D008099:Liver / Q000098:blood supply* / Q000201:enzymology* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008930:Mitochondria, Liver / Q000201:enzymology* / Q000473:pathology; D024101:Mitochondrial Proteins / Q000378:metabolism; D054465:Peroxiredoxin VI / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport; D040901:Proteomics; D015427:Reperfusion Injury / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D013997:Time Factors
D024101:Mitochondrial Proteins; D006861:Hydrogen Peroxide; D054465:Peroxiredoxin VI; C515983:Prdx6 protein, mouse; D042967:Electron Transport Complex I