Methylglyoxal-induced mitochondrial dysfunction in vascular smooth muscle cells.
The effects of methylglyoxal (MG) on mitochondria with specific foci on peroxynitrite (ONOO(-)) production, manganese superoxide dismutase (MnSOD) activity, and mitochondrial functions in vascular smooth muscle A-10 cells were investigated. Mitochondrial MG content was significantly increased after A-10 cells were treated with exogenous MG, and so did advanced glycated endproducts (AGEs) formation, indicated by the appearance of N(epsilon)-(carboxyethyl) lysine, in A-10 cells. The levels of mitochondrial reactive oxygen species (mtROS) and ONOO(-) were significantly increased by MG treatment. Application of ONOO(-) specific scavenger uric acid lowered the level of mtROS. MG significantly enhanced the production of mitochondrial superoxide (O(2)(-)) and nitric oxide (NO), which were inhibited by SOD mimic 4-hydroxy-tempo and mitochondrial nitric oxide synthase (mtNOS) specific inhibitor 7-nitroindazole, respectively. The activity of MnSOD was decreased by MG treatment. Furthermore, MG decreased respiratory complex III activity and ATP synthesis in mitochondria, indicating an impaired mitochondrial respiratory chain. AGEs cross-link breaker alagebrium reversed all aforementioned mitochondrial effects of MG. Our data demonstrated that mitochondrial function is under the control of MG. By inhibiting Complex III activity, MG induces mitochondrial oxidative stress and reduces ATP production. These discoveries will help unmask molecular mechanisms for various MG-induced mitochondrial dysfunction-related cellular disorders.
Department of Pharmacology, College of Medicine, University of Saskatchewan, 107 Wiggins Road, Saskatoon, SK, Canada.
Hui
H
Wang
Jianghai
J
Liu
Lingyun
L
Wu
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000166:cytology / Q000187:drug effects; D002460:Cell Line; D042967:Electron Transport Complex I / Q000378:metabolism; D014450:Electron Transport Complex III / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D009569:Nitric Oxide / Q000378:metabolism; D011765:Pyruvaldehyde / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism
D017382:Reactive Oxygen Species; D013481:Superoxides; D009569:Nitric Oxide; D011765:Pyruvaldehyde; D000255:Adenosine Triphosphate; D013482:Superoxide Dismutase; D042967:Electron Transport Complex I; D014450:Electron Transport Complex III