title: Glycation of mitochondrial proteins from diabetic rat kidney is associated with excess superoxide formation.
abstract: Chronic hyperglycemia causes structural alterations of proteins through the Maillard reaction. In diabetes, methylglyoxal (MGO)-induced hydroimidazolones are the predominant modification. In contrast to acute hyperglycemia, mitochondrial respiration is depressed in chronic diabetes. To determine whether MGO-derived protein modifications result in abnormalities in mitochondrial bioenergetics and superoxide formation, proteomics and functional studies were performed in renal cortical mitochondria isolated from rats with 2, 6, and 12 mo of streptozotocin-induced diabetes. MGO-modified proteins belonged to the following two pathways: 1) oxidative phosphorylation and 2) fatty acid beta-oxidation. Two of these proteins were identified as components of respiratory complex III, the major site of superoxide production in health and disease. Mitochondria from rats with diabetes exhibited a diminution of oxidative phosphorylation. A decrease in the respiratory complex III activity was significantly correlated with the quantity of MGO-derived hydroimidazolone present on mitochondrial proteins in both diabetic and control animals. In diabetes, isolated renal mitochondria produced significantly increased quantities of superoxide and showed evidence of oxidative damage. Administration of aminoguanidine improved mitochondrial respiration and complex III activity and decreased oxidative damage to mitochondrial proteins. Therefore, posttranslational modifications of mitochondrial proteins by MGO may represent pathogenic events leading to mitochondria-induced oxidative stress in the kidney in chronic diabetes.
authors.affiliation: Deparment of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Mariana G
authors.initials: MG
authors.lastname: Rosca
authors.forename: Tiberiu G
authors.initials: TG
authors.lastname: Mustata
authors.forename: Michael T
authors.initials: MT
authors.lastname: Kinter
authors.forename: Aylin M
authors.initials: AM
authors.lastname: Ozdemir
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Kern
authors.forename: Luke I
authors.initials: LI
authors.lastname: Szweda
authors.forename: Michael
authors.initials: M
authors.lastname: Brownlee
authors.forename: Vincent M
authors.initials: VM
authors.lastname: Monnier
authors.forename: Miriam F
authors.initials: MF
authors.lastname: Weiss
mesh_terms: D019297:2,4-Dinitrophenol / Q000494:pharmacology; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000378:metabolism*; D015180:Electrophoresis, Gel, Two-Dimensional; D004734:Energy Metabolism; D005227:Fatty Acids / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006146:Guanidines / Q000494:pharmacology; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000187:drug effects / Q000378:metabolism*; D009097:Multienzyme Complexes / Q000378:metabolism; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D016877:Oxidants / Q000378:metabolism*; D010084:Oxidation-Reduction; D010085:Oxidative Phosphorylation; D018384:Oxidative Stress / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D011765:Pyruvaldehyde / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew; D013481:Superoxides / Q000378:metabolism*; D014475:Uncoupling Agents / Q000494:pharmacology
chemical_list: D001786:Blood Glucose; D005227:Fatty Acids; D006146:Guanidines; D024101:Mitochondrial Proteins; D009097:Multienzyme Complexes; D016877:Oxidants; D014475:Uncoupling Agents; D013481:Superoxides; D011765:Pyruvaldehyde; C023107:NADH oxidase; D009247:NADH, NADPH Oxidoreductases; D005947:Glucose; D019297:2,4-Dinitrophenol; C004479:pimagedine