title: Mitochondrial dysfunction in the type 2 diabetic heart is associated with alterations in spatially distinct mitochondrial proteomes.
abstract: Cardiac complications and heart failure are the leading cause of death in type 2 diabetic patients. Mitochondrial dysfunction is central in the pathogenesis of the type 2 diabetic heart. However, it is unclear whether this dysfunction is specific for a particular subcellular region. The purpose of this study was to determine whether mitochondrial dysfunction in the type 2 diabetic heart is specific to a spatially distinct subset of mitochondria. We investigated mitochondrial morphology, function, and proteomic composition of subsarcolemmal mitochondria (SSM) and interfibrillar mitochondria (IFM) in 18-wk-old db/db mice. Oxidative damage was assessed in subpopulations through the measurement of lipid peroxidation byproducts and nitrotyrosine residues. Proteomic profiles and posttranslational modifications were assessed in mitochondrial subpopulations using iTRAQ and multi-dimensional protein identification technologies, respectively. SSM from db/db hearts had altered morphology, including a decrease in size and internal complexity, whereas db/db IFM were increased in internal complexity. Db/db SSM displayed decreased state 3 respiration rates, electron transport chain activities, ATP synthase activities, and mitochondrial membrane potential and increased oxidative damage, with no change in IFM. Proteomic assessment revealed a greater impact on db/db SSM compared with db/db IFM. Inner mitochondrial membrane proteins, including electron transport chain, ATP synthesis, and mitochondrial protein import machinery, were predominantly decreased. We provide evidence that mitochondrial dysfunction in the type 2 diabetic heart is associated with a specific subcellular locale. Furthermore, mitochondrial morphological and functional indexes are impacted differently during type 2 diabetic insult and may result from the modulation of spatially distinct mitochondrial proteomes.
authors.affiliation: West Virginia Univ. School of Medicine, Div. of Exercise Physiology, Center for Cardiovascular and Respiratory Sciences, 1 Medical Center Dr., Morgantown, WV 26506, USA.
authors.forename: Erinne R
authors.initials: ER
authors.lastname: Dabkowski
authors.forename: Walter A
authors.initials: WA
authors.lastname: Baseler
authors.forename: Courtney L
authors.initials: CL
authors.lastname: Williamson
authors.forename: Matthew
authors.initials: M
authors.lastname: Powell
authors.forename: Trust T
authors.initials: TT
authors.lastname: Razunguzwa
authors.forename: Jefferson C
authors.initials: JC
authors.lastname: Frisbee
authors.forename: John M
authors.initials: JM
authors.lastname: Hollander
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D019069:Cell Respiration; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D004579:Electron Transport; D045222:Electron Transport Chain Complex Proteins / Q000378:metabolism; D007473:Ion Channels / Q000378:metabolism; D015227:Lipid Peroxidation; D008297:Male; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008929:Mitochondria, Heart / Q000378:metabolism* / Q000473:pathology; D000226:Mitochondrial ADP, ATP Translocases / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism*; D025261:Mitochondrial Proton-Translocating ATPases / Q000378:metabolism; D053142:Mitochondrial Size; D018384:Oxidative Stress; D011499:Protein Processing, Post-Translational; D020543:Proteome; D040901:Proteomics / Q000379:methods; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D000071247:Uncoupling Protein 3
chemical_list: D000975:Antioxidants; D045222:Electron Transport Chain Complex Proteins; D007473:Ion Channels; D024101:Mitochondrial Proteins; D020543:Proteome; D000071247:Uncoupling Protein 3; C002744:3-nitrotyrosine; D014443:Tyrosine; D000226:Mitochondrial ADP, ATP Translocases; D025261:Mitochondrial Proton-Translocating ATPases