title: Mitochondrial complex I defect and increased fatty acid oxidation enhance protein lysine acetylation in the diabetic heart.
abstract: OBJECTIVE
  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.
  
  
  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 long-chain 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 α may be responsible for the increased fatty acid oxidation in the diabetic heart.
  
  
  CONCLUSIONS
  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 inflexibility of the diabetic heart.
authors.affiliation: Department of Nutrition, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: Edwin J
authors.initials: EJ
authors.lastname: Vazquez
authors.affiliation: Department of Physiology, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Berthiaume
authors.affiliation: Department of Foundational Sciences, Central Michigan University College of Medicine, Mount Pleasant, MI, USA.
authors.forename: Vasudeva
authors.initials: V
authors.lastname: Kamath
authors.affiliation: Department of Foundational Sciences, Central Michigan University College of Medicine, Mount Pleasant, MI, USA.
authors.forename: Olisaemeka
authors.initials: O
authors.lastname: Achike
authors.affiliation: Department of Foundational Sciences, Central Michigan University College of Medicine, Mount Pleasant, MI, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Buchanan
authors.affiliation: Department of Pharmacology, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: Monica M
authors.initials: MM
authors.lastname: Montano
authors.affiliation: Department of Physiology, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: Margaret P
authors.initials: MP
authors.lastname: Chandler
authors.affiliation: Center for Proteomics and Bioinformatics, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: Masaru
authors.initials: M
authors.lastname: Miyagi
authors.affiliation: Department of Foundational Sciences, Central Michigan University College of Medicine, Mount Pleasant, MI, USA rosca1g@cmich.edu.
authors.forename: Mariana G
authors.initials: MG
authors.lastname: Rosca
mesh_terms: D000107:Acetylation; D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000150:complications / Q000378:metabolism*; D004195:Disease Models, Animal; D042967:Electron Transport Complex I / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism*; D006321:Heart / Q000503:physiopathology; D050356:Lipid Metabolism / Q000502:physiology; D008239:Lysine / Q000378:metabolism; D008297:Male; D008929:Mitochondria, Heart / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism*; D010084:Oxidation-Reduction; D011917:Rats, Inbred Lew
chemical_list: D005227:Fatty Acids; D024101:Mitochondrial Proteins; D042967:Electron Transport Complex I; D008239:Lysine
keywords: Diabetes; Heart; Lysine acetylation; Mitochondria; Oxidative phosphorylation