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1 Department of Medicine, Case Western Reserve University, Cleveland, OH, USA
2 Departments of Pathology and Biochemistry, Case Western Reserve University, Cleveland, OH, USA
3 Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA
4 Department of Physiology, Case Western Reserve University, Cleveland, OH, USA
5 Department of Medicine and Pathology, and Diabetes Research and Training Center, Albert Einstein College of Medicine, Bronx, NY, USA
* To whom correspondence should be addressed. E-mail: maf3{at}po.cwru.edu.
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 if 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 (STZ)-
induced diabetes. MGO-modified proteins belonged to two pathways: 1) Oxidative
phosphorylation, and 2) Fatty acid 
-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, post-translational modifications of
mitochondrial proteins by MGO may represent pathogenic events leading to mitochondriainduced
oxidative stress in the kidney in chronic diabetes.
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