Changes in mitochondrial morphology and organization can enhance energy supply from mitochondrial oxidative phosphorylation in diabetic cardiomyopathy.

Diabetic cardiomyopathy is accompanied by metabolic and ultrastructural alterations, but the impact of the structural changes on metabolism itself is yet to be determined. Morphometric analysis of mitochondrial shape and spatial organization within transverse sections of cardiomyocytes from control and streptozotocin-induced type I diabetic Sprague-Dawley rats revealed that mitochondria are 20% smaller in size while their spatial density increases by 53% in diabetic cells relative to control myocytes. Diabetic cells formed larger clusters of mitochondria (60% more mitochondria per cluster) and the effective surface-to-volume ratio of these clusters increased by 22.5%. Using a biophysical computational model we found that this increase can have a moderate compensatory effect by increasing the availability of ATP in the cytosol when ATP synthesis within the mitochondrial matrix is compromised.

[1]  J. Wada,et al.  Mitochondrial Dynamics and Mitochondrial Dysfunction in Diabetes. , 2016, Acta medica Okayama.

[2]  S. Cortassa,et al.  Protective mechanisms of mitochondria and heart function in diabetes. , 2015, Antioxidants & redox signaling.

[3]  R. Gottlieb,et al.  Myocardial autophagic energy stress responses--macroautophagy, mitophagy, and glycophagy. , 2015, American journal of physiology. Heart and circulatory physiology.

[4]  Antonis A Armoundas,et al.  Mitochondrial networks in cardiac myocytes reveal dynamic coupling behavior. , 2015, Biophysical journal.

[5]  D. Wallace,et al.  Trans-mitochondrial coordination of cristae at regulated membrane junctions , 2015, Nature Communications.

[6]  Peter J. Hunter,et al.  OpenCOR: a modular and interoperable approach to computational biology , 2015, Front. Physiol..

[7]  D. Loiselle,et al.  Mitochondrial inefficiencies and anoxic ATP hydrolysis capacities in diabetic rat heart. , 2014, American journal of physiology. Cell physiology.

[8]  J. Hollander,et al.  Physiological and structural differences in spatially distinct subpopulations of cardiac mitochondria: influence of cardiac pathologies. , 2014, American journal of physiology. Heart and circulatory physiology.

[9]  D. Bernlohr,et al.  Insulin Stimulates Mitochondrial Fusion and Function in Cardiomyocytes via the Akt-mTOR-NFκB-Opa-1 Signaling Pathway , 2013, Diabetes.

[10]  D. Turnbull,et al.  Acute exercise remodels mitochondrial membrane interactions in mouse skeletal muscle , 2013, Journal of applied physiology.

[11]  Y. Yoon,et al.  Mitochondrial morphology in metabolic diseases. , 2013, Antioxidants & redox signaling.

[12]  G. Dorn.  Mitochondrial dynamics in heart disease. , 2013, Biochimica et biophysica acta.

[13]  M. Orešič,et al.  Mitofusin 2 (Mfn2) links mitochondrial and endoplasmic reticulum function with insulin signaling and is essential for normal glucose homeostasis , 2012, Proceedings of the National Academy of Sciences.

[14]  M. Irwin,et al.  PKCβ inhibition with ruboxistaurin reduces oxidative stress and attenuates left ventricular hypertrophy and dysfunction in rats with streptozotocin-induced diabetes. , 2012, Clinical science.

[15]  T. Murohara,et al.  Association of diabetes mellitus with myocardial collagen accumulation and relaxation impairment in patients with dilated cardiomyopathy. , 2011, Diabetes research and clinical practice.

[16]  L. Scorrano,et al.  During autophagy mitochondria elongate, are spared from degradation and sustain cell viability , 2011, Nature Cell Biology.

[17]  Michael O'Sullivan,et al.  Stochastic modelling of cardiac cell structure , 2010, 2010 Annual International Conference of the IEEE Engineering in Medicine and Biology.

[18]  E. Abel,et al.  Mitochondria in the diabetic heart. , 2010, Cardiovascular research.

[19]  T. Gillette,et al.  Diabetic Cardiomyopathy: Mechanisms and Therapeutic Targets. , 2010, Drug discovery today. Disease mechanisms.

[20]  A. Makino,et al.  Mitochondrial fragmentation and superoxide anion production in coronary endothelial cells from a mouse model of type 1 diabetes , 2010, Diabetologia.

[21]  R. Ritchie,et al.  Reactive oxygen species and insulin‐resistant cardiomyopathy , 2010, Clinical and experimental pharmacology & physiology.

[22]  S. Alway,et al.  Enhanced apoptotic propensity in diabetic cardiac mitochondria: influence of subcellular spatial location. , 2010, American journal of physiology. Heart and circulatory physiology.

[23]  P. Sharma.  Mechanics of materials. , 2010, Technology and health care : official journal of the European Society for Engineering and Medicine.

[24]  E. Crampin,et al.  A thermodynamic model of the cardiac sarcoplasmic/endoplasmic Ca(2+) (SERCA) pump. , 2009, Biophysical journal.

[25]  S. Leonard,et al.  Diabetic cardiomyopathy-associated dysfunction in spatially distinct mitochondrial subpopulations. , 2009, American journal of physiology. Heart and circulatory physiology.

[26]  V. Kupriyanov,et al.  Potassium fluxes, energy metabolism, and oxygenation in intact diabetic rat hearts under normal and stress conditions. , 2008, Canadian journal of physiology and pharmacology.

[27]  Y. Yoon,et al.  Mitochondrial fission mediates high glucose-induced cell death through elevated production of reactive oxygen species. , 2008, Cardiovascular research.

[28]  G. Cooper,et al.  Characterization of proteomic changes in cardiac mitochondria in streptozotocin‐diabetic rats using iTRAQ™ isobaric tags , 2007, Proteomics. Clinical applications.

[29]  Y. Yoon,et al.  Increased production of reactive oxygen species in hyperglycemic conditions requires dynamic change of mitochondrial morphology. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[30]  Daniel A. Beard,et al.  A Biophysical Model of the Mitochondrial Respiratory System and Oxidative Phosphorylation , 2005, PLoS Comput. Biol..

[31]  L. Stehno-Bittel,et al.  Exercise attenuates diabetes-induced ultrastructural changes in rat cardiac tissue. , 2004, Medicine and science in sports and exercise.

[32]  W. Pierce,et al.  Cardiac mitochondrial damage and biogenesis in a chronic model of type 1 diabetes. , 2004, American journal of physiology. Endocrinology and metabolism.

[33]  Ken‐ichi Suzuki,et al.  Ultrastructural alterations in cardiac muscle of diabetic BB Wistar rats , 2004, Virchows Archiv A.

[34]  F. Murad,et al.  Protein Tyrosine Nitration in the Mitochondria from Diabetic Mouse Heart , 2003, Journal of Biological Chemistry.

[35]  Michael Marko,et al.  Topology of the Mitochondrial Inner Membrane: Dynamics and Bioenergetic Implications , 2001, IUBMB life.

[36]  K. Welt,et al.  The influence of hypoxia on the myocardium of experimentally diabetic rats with and without protection by Ginkgo biloba extract. III: Ultrastructural investigations on mitochondria. , 2001, Experimental and toxicologic pathology : official journal of the Gesellschaft fur Toxikologische Pathologie.

[37]  M. Vendelin,et al.  Regulation of mitochondrial respiration in heart cells analyzed by reaction-diffusion model of energy transfer. , 2000, American journal of physiology. Cell physiology.

[38]  V. Saks,et al.  Compartmentalized energy transfer in cardiomyocytes: use of mathematical modeling for analysis of in vivo regulation of respiration. , 1997, Biophysical journal.

[39]  J R Kremer,et al.  Computer visualization of three-dimensional image data using IMOD. , 1996, Journal of structural biology.

[40]  J. McNeill,et al.  A Functional and Ultrastructural Analysis of Experimental Diabetic Rat Myocardium: Manifestation of a Cardiomyopathy , 1985, Diabetes.