title: 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.
authors.affiliation: Department of Biological Sciences and Hull York Medical School, University of Hull, Kingston-upon-Hull, United Kingdom; and.
authors.forename: David
authors.initials: D
authors.lastname: Taylor
authors.affiliation: Department of Renal Medicine, Hull and East Yorkshire Hospital NHS Trust, Kingston-upon-Hull, United Kingdom.
authors.forename: Sunil
authors.initials: S
authors.lastname: Bhandari
authors.affiliation: Department of Biological Sciences and Hull York Medical School, University of Hull, Kingston-upon-Hull, United Kingdom; and a.m.seymour@hull.ac.uk.
authors.forename: Anne-Marie L
authors.initials: AM
authors.lastname: Seymour
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D009202:Cardiomyopathies / Q000209:etiology* / Q000378:metabolism; D019069:Cell Respiration; D002478:Cells, Cultured; D004195:Disease Models, Animal; D066298:In Vitro Techniques; D008297:Male; D008928:Mitochondria / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism*; D000083162:Mitochondrial Permeability Transition Pore; D015428:Myocardial Reperfusion Injury / Q000209:etiology* / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism; D018384:Oxidative Stress; D017207:Rats, Sprague-Dawley; D014511:Uremia / Q000150:complications* / Q000378:metabolism
chemical_list: D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D002118:Calcium
keywords: chronic kidney disease; mitochondrial dysfunction; mitochondrial permeability transition pore; uremic cardiomyopathy