Reversal of mitochondrial proteomic loss in Type 1 diabetic heart with overexpression of phospholipid hydroperoxide glutathione peroxidase

Am J Physiol Regul Integr Comp Physiol. 2013 Apr 1;304(7):R553-65. doi: 10.1152/ajpregu.00249.2012. Epub 2013 Feb 13.


Mitochondrial dysfunction is a contributor to diabetic cardiomyopathy. Previously, we observed proteomic decrements within the inner mitochondrial membrane (IMM) and matrix of diabetic cardiac interfibrillar mitochondria (IFM) correlating with dysfunctional mitochondrial protein import. The goal of this study was to determine whether overexpression of mitochondria phospholipid hydroperoxide glutathione peroxidase 4 (mPHGPx), an antioxidant enzyme capable of scavenging membrane-associated lipid peroxides in the IMM, could reverse proteomic alterations, dysfunctional protein import, and ultimately, mitochondrial dysfunction associated with the diabetic heart. MPHGPx transgenic mice and controls were made diabetic by multiple low-dose streptozotocin injections and examined after 5 wk of hyperglycemia. Five weeks after hyperglycemia onset, in vivo analysis of cardiac contractile function revealed decreased ejection fraction and fractional shortening in diabetic hearts that was reversed with mPHGPx overexpression. MPHGPx overexpression increased electron transport chain function while attenuating hydrogen peroxide production and lipid peroxidation in diabetic mPHGPx IFM. MPHGPx overexpression lessened proteomic loss observed in diabetic IFM. Posttranslational modifications, including oxidations and deamidations, were attenuated in diabetic IFM with mPHGPx overexpression. Mitochondrial protein import dysfunction in diabetic IFM was reversed with mPHGPx overexpression correlating with protein import constituent preservation. Ingenuity Pathway Analyses indicated that oxidative phosphorylation, tricarboxylic acid cycle, and fatty acid oxidation processes most influenced in diabetic IFM were preserved by mPHGPx overexpression. Specific mitochondrial networks preserved included complex I and II, mitochondrial ultrastructure, and mitochondrial protein import. These results indicate that mPHGPx overexpression can preserve the mitochondrial proteome and provide cardioprotective benefits to the diabetic heart.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Biological Transport
  • Diabetes Mellitus, Experimental / complications
  • Diabetes Mellitus, Experimental / metabolism*
  • Diabetes Mellitus, Type 1 / complications
  • Diabetes Mellitus, Type 1 / metabolism*
  • Diabetic Cardiomyopathies / complications
  • Diabetic Cardiomyopathies / metabolism*
  • Female
  • Gene Expression Regulation, Enzymologic / physiology*
  • Glutathione Peroxidase / genetics
  • Glutathione Peroxidase / metabolism*
  • Lipid Peroxidation
  • Male
  • Mass Spectrometry
  • Mice
  • Mice, Transgenic
  • Mitochondria, Heart / enzymology
  • Mitochondria, Heart / genetics
  • Mitochondria, Heart / metabolism*
  • Oxidative Stress
  • Phospholipid Hydroperoxide Glutathione Peroxidase
  • Proteomics
  • Reactive Oxygen Species / metabolism


  • Reactive Oxygen Species
  • Phospholipid Hydroperoxide Glutathione Peroxidase
  • Glutathione Peroxidase