title: Glyoxalase-1 prevents mitochondrial protein modification and enhances lifespan in Caenorhabditis elegans.
abstract: Studies of mutations affecting lifespan in Caenorhabditis elegans show that mitochondrial generation of reactive oxygen species (ROS) plays a major causative role in organismal aging. Here, we describe a novel mechanism for regulating mitochondrial ROS production and lifespan in C. elegans: progressive mitochondrial protein modification by the glycolysis-derived dicarbonyl metabolite methylglyoxal (MG). We demonstrate that the activity of glyoxalase-1, an enzyme detoxifying MG, is markedly reduced with age despite unchanged levels of glyoxalase-1 mRNA. The decrease in enzymatic activity promotes accumulation of MG-derived adducts and oxidative stress markers, which cause further inhibition of glyoxalase-1 expression. Over-expression of the C. elegans glyoxalase-1 orthologue CeGly decreases MG modifications of mitochondrial proteins and mitochondrial ROS production, and prolongs C. elegans lifespan. In contrast, knock-down of CeGly increases MG modifications of mitochondrial proteins and mitochondrial ROS production, and decreases C. elegans lifespan.
authors.affiliation: Department of Medicine I and Clinical Chemistry, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Morcos
authors.forename: Xueliang
authors.initials: X
authors.lastname: Du
authors.forename: Friederike
authors.initials: F
authors.lastname: Pfisterer
authors.forename: Harald
authors.initials: H
authors.lastname: Hutter
authors.forename: Ahmed A R
authors.initials: AA
authors.lastname: Sayed
authors.forename: Paul
authors.initials: P
authors.lastname: Thornalley
authors.forename: Naila
authors.initials: N
authors.lastname: Ahmed
authors.forename: John
authors.initials: J
authors.lastname: Baynes
authors.forename: Suzanne
authors.initials: S
authors.lastname: Thorpe
authors.forename: Georgi
authors.initials: G
authors.lastname: Kukudov
authors.forename: Andreas
authors.initials: A
authors.lastname: Schlotterer
authors.forename: Farastuk
authors.initials: F
authors.lastname: Bozorgmehr
authors.forename: Randa Abd
authors.initials: RA
authors.lastname: El Baki
authors.forename: David
authors.initials: D
authors.lastname: Stern
authors.forename: Frank
authors.initials: F
authors.lastname: Moehrlen
authors.forename: Youssef
authors.initials: Y
authors.lastname: Ibrahim
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Oikonomou
authors.forename: Andreas
authors.initials: A
authors.lastname: Hamann
authors.forename: Christian
authors.initials: C
authors.lastname: Becker
authors.forename: Martin
authors.initials: M
authors.lastname: Zeier
authors.forename: Vedat
authors.initials: V
authors.lastname: Schwenger
authors.forename: Nexhat
authors.initials: N
authors.lastname: Miftari
authors.forename: Per
authors.initials: P
authors.lastname: Humpert
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Hammes
authors.forename: Markus
authors.initials: M
authors.lastname: Buechler
authors.forename: Angelika
authors.initials: A
authors.lastname: Bierhaus
authors.forename: Michael
authors.initials: M
authors.lastname: Brownlee
authors.forename: Peter P
authors.initials: PP
authors.lastname: Nawroth
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000201:enzymology*; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism; D004791:Enzyme Inhibitors; D025461:Feedback, Physiological; D015870:Gene Expression; D007791:Lactoylglutathione Lyase / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000172:deficiency*; D008136:Longevity; D008928:Mitochondria / Q000201:enzymology*; D024101:Mitochondrial Proteins / Q000378:metabolism; D009154:Mutation; D010085:Oxidative Phosphorylation; D018384:Oxidative Stress; D046188:Protein Modification, Translational; D011765:Pyruvaldehyde / Q000378:metabolism; D018510:RNA, Helminth; D012333:RNA, Messenger / Q000032:analysis; D017382:Reactive Oxygen Species / Q000032:analysis / Q000378:metabolism
chemical_list: D029742:Caenorhabditis elegans Proteins; D004791:Enzyme Inhibitors; D024101:Mitochondrial Proteins; D018510:RNA, Helminth; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D011765:Pyruvaldehyde; D007791:Lactoylglutathione Lyase