Glycation of mitochondrial proteins from diabetic rat kidney is associated with excess superoxide formation

Mariana G. Rosca, Tiberiu G. Mustata, Michael T. Kinter, Aylin M. Ozdemir, Timothy S. Kern, Luke I. Szweda, Michael Brownlee, Vincent M. Monnier, Miriam F. Weiss

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256 Scopus citations

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 β-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.

Original languageEnglish (US)
Pages (from-to)F420-F430
JournalAmerican Journal of Physiology - Renal Physiology
Volume289
Issue number2 58-2
DOIs
StatePublished - Aug 2005

Keywords

  • Complex III
  • Methylglyoxal
  • Nephropathy
  • Proteomics

ASJC Scopus subject areas

  • Physiology
  • Urology

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    Rosca, M. G., Mustata, T. G., Kinter, M. T., Ozdemir, A. M., Kern, T. S., Szweda, L. I., Brownlee, M., Monnier, V. M., & Weiss, M. F. (2005). Glycation of mitochondrial proteins from diabetic rat kidney is associated with excess superoxide formation. American Journal of Physiology - Renal Physiology, 289(2 58-2), F420-F430. https://doi.org/10.1152/ajprenal.00415.2004