Glyoxalase-1 prevents mitochondrial protein modification and enhances lifespan in Caenorhabditis elegans.
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.
Morcos
Michael
M
Department of Medicine I and Clinical Chemistry, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
Du
Xueliang
X
Pfisterer
Friederike
F
Hutter
Harald
H
Sayed
Ahmed A R
AA
Thornalley
Paul
P
Ahmed
Naila
N
Baynes
John
J
Thorpe
Suzanne
S
Kukudov
Georgi
G
Schlotterer
Andreas
A
Bozorgmehr
Farastuk
F
El Baki
Randa Abd
RA
Stern
David
D
Moehrlen
Frank
F
Ibrahim
Youssef
Y
Oikonomou
Dimitrios
D
Hamann
Andreas
A
Becker
Christian
C
Zeier
Martin
M
Schwenger
Vedat
V
Miftari
Nexhat
N
Humpert
Per
P
Hammes
Hans-Peter
HP
Buechler
Markus
M
Bierhaus
Angelika
A
Brownlee
Michael
M
Nawroth
Peter P
PP
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
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