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 week old db/db mice. Oxidative damage was assessed in subpopulations through measuring lipid peroxidation by-products and nitrotyrosine residues. Proteomic profiles and post-translational modifications (PTM) were assessed in mitochondrial subpopulations utilizing iTRAQ™ and MudPIT technologies, respectively. SSM from db/db hearts had altered morphology including a decrease in size and internal complexity, while db/db IFM were increased in internal complexity. Db/db SSM displayed decreased state 3 respiration rates, electron transport chain (ETC) activities, ATP synthase activities, mitochondrial membrane potential (ΔΨm), and increased oxidative damage, with no change in IFM. Proteomic assessment revealed a greater impact on db/db SSM as compared to db/db IFM. Inner mitochondrial membrane (IMM) proteins including ETC, 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. Further, mitochondrial morphological and functional indices are impacted differently during type 2 diabetic insult, and may result from modulation of spatially distinct mitochondrial proteomes.
- Copyright © 2010, American Journal of Physiology - Heart and Circulatory Physiology