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.