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Mitochondrial dysfunction in uremic cardiomyopathy.

Abstract
Uremic cardiomyopathy (UCM) is characterized by metabolic remodelling, compromised energetics, and loss of insulin-mediated cardioprotection, which result in unsustainable adaptations and heart failure. However, the role of mitochondria and the susceptibility of mitochondrial permeability transition pore (mPTP) formation in ischemia-reperfusion injury (IRI) in UCM are unknown. Using a rat model of chronic uremia, we investigated the oxidative capacity of mitochondria in UCM and their sensitivity to ischemia-reperfusion mimetic oxidant and calcium stressors to assess the susceptibility to mPTP formation. Uremic animals exhibited a 45% reduction in creatinine clearance (P < 0.01), and cardiac mitochondria demonstrated uncoupling with increased state 4 respiration. Following IRI, uremic mitochondria exhibited a 58% increase in state 4 respiration (P < 0.05), with an overall reduction in respiratory control ratio (P < 0.01). Cardiomyocytes from uremic animals displayed a 30% greater vulnerability to oxidant-induced cell death determined by FAD autofluorescence (P < 0.05) and reduced mitochondrial redox state on exposure to 200 μM H2O2 (P < 0.01). The susceptibility to calcium-induced permeability transition showed that maximum rates of depolarization were enhanced in uremia by 79%. These results demonstrate that mitochondrial respiration in the uremic heart is chronically uncoupled. Cardiomyocytes in UCM are characterized by a more oxidized mitochondrial network, with greater susceptibility to oxidant-induced cell death and enhanced vulnerability to calcium-induced mPTP formation. Collectively, these findings indicate that mitochondrial function is compromised in UCM with increased vulnerability to calcium and oxidant-induced stressors, which may underpin the enhanced predisposition to IRI in the uremic heart.
AuthorsDavid Taylor, Sunil Bhandari, Anne-Marie L Seymour
JournalAmerican journal of physiology. Renal physiology (Am J Physiol Renal Physiol) Vol. 308 Issue 6 Pg. F579-87 (Mar 15 2015) ISSN: 1522-1466 [Electronic] United States
PMID25587120 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2015 the American Physiological Society.
Chemical References
  • Mitochondrial Membrane Transport Proteins
  • Mitochondrial Permeability Transition Pore
  • Calcium
Topics
  • Animals
  • Calcium (metabolism)
  • Cardiomyopathies (etiology, metabolism)
  • Cell Respiration
  • Cells, Cultured
  • Disease Models, Animal
  • In Vitro Techniques
  • Male
  • Mitochondria (metabolism)
  • Mitochondrial Membrane Transport Proteins (metabolism)
  • Mitochondrial Permeability Transition Pore
  • Myocardial Reperfusion Injury (etiology, metabolism)
  • Myocytes, Cardiac (metabolism)
  • Oxidative Stress
  • Rats, Sprague-Dawley
  • Uremia (complications, metabolism)

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