Glycation of mitochondrial proteins from diabetic rat kidney is associated with excess superoxide formation.
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.
Rosca
Mariana G
MG
Deparment of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
Mustata
Tiberiu G
TG
Kinter
Michael T
MT
Ozdemir
Aylin M
AM
Kern
Timothy S
TS
Szweda
Luke I
LI
Brownlee
Michael
M
Monnier
Vincent M
VM
Weiss
Miriam F
MF
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
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