Mitochondrial dysfunction in uremic cardiomyopathy

• Published in: American journal of physiology. Renal physiology 2015-03, Vol.308 (6), p.F579-F587
• Main Authors: Taylor, David, Bhandari, Sunil, Seymour, Anne-Marie L
• Format: Article
• Language: English
• Subjects: Animals; Calcium; Calcium - metabolism; Cardiomyocytes; Cardiomyopathies - etiology; Cardiomyopathies - metabolism; Cell Respiration; Cells, Cultured; Disease Models, Animal; In Vitro Techniques; Kidney diseases; Male; Mitochondria; Mitochondria - metabolism; Mitochondrial Membrane Transport Proteins - metabolism; Myocardial Reperfusion Injury - etiology; Myocardial Reperfusion Injury - metabolism; Myocytes, Cardiac - metabolism; Oxidative Stress; Rats, Sprague-Dawley; Rodents; Uremia - complications; Uremia - metabolism
• ISSN: 1931-857X; 1522-1466
• DOI: 10.1152/ajprenal.00442.2014

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.