Mitochondrial complex i defect and increased fatty acid oxidation enhance protein lysine acetylation in the diabetic heart

Edwin J. Vazquez, Jessica M. Berthiaume, Vasudeva Kamath, Olisaemeka Achike, Elizabeth Buchanan, Monica M. Montano, Margaret P. Chandler, Masaru Miyagi, Mariana G. Rosca

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59 Scopus citations


Aims Cardiomyopathy is a major complication of diabetes. Our study was aimed to identify the sites of mitochondrial dysfunction and delineate its consequences on mitochondrial metabolism in a model of type 1 diabetes. Methods and results Diabetes was induced by streptozotocin injection to male Lewis rats.We found a decrease in mitochondrial biogenesis pathway and electron transport chain complex assembly that targets Complex I. Oxidation of Complex II and longchain fatty acid substrates support the electron leak and superoxide production. Mitochondrial defects do not limit fatty acid oxidation as the heart's preferred energy source indicating that the diabetic heart has a significant reserve in Complex I-and II-supported ATP production. Both mitochondrial fatty acid oxidation and Complex I defect are responsible for increased protein lysine acetylation despite an unchanged amount of the NAD+-dependent mitochondrial deacetylase sirt3.We quantitatively analysed mitochondrial lysine acetylation post-translational modifications and identified that the extent of lysine acetylation on 54 sites in 22 mitochondrial proteins is higher in diabetes compared with the same sites in the control. The increased lysine acetylation of the mitochondrial trifunctional protein subunit a may be responsible for the increased fatty acid oxidation in the diabetic heart. Conclusion We identified the specific defective sites in the electron transport chain responsible for the decreased mitochondrial oxidative phosphorylation in the diabetic heart. Mitochondrial protein lysine acetylation is the common consequence of both increased fatty acid oxidation and mitochondrial Complex I defect, and may be responsible for the metabolic in-flexibility of the diabetic heart.

Original languageEnglish
Pages (from-to)453-465
Number of pages13
JournalCardiovascular Research
Issue number4
StatePublished - Sep 1 2015


  • Diabetes
  • Heart
  • Lysine acetylation
  • Mitochondria
  • Oxidative phosphorylation


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