Uncoupling proteins in the human heart

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Results of a study in this week’s issue of THE LANCET suggest that respiratory uncoupling and reduced substrate availability might lead to energy deficiency in heart failure.

ATP production depends on the energy of the proton gradient across the mitochondrial inner membrane. ATP synthesis is impaired if this gradient is substantially reduced. Uncoupling proteins (UCP) lower the gradient by allowing protons to re-enter the mitochondrial matrix; this produces heat rather than ATP. In isolated rat cardiomyocytes, mRNA levels of two UCP isoforms in the heart (UCP2 and UCP3) increase and concentrations of the insulin-responsive glucose transporter (GLUT4) fall in the presence of long-chain free fatty acids.

To investigate the association between energetic and metabolic abnormalities of the human heart, Andrew J Murray (University of Oxford, UK) and colleagues analysed fasting arterial blood samples from 39 patients undergoing coronary artery bypass graft surgery. In the presence of fasting free-fatty-acid concentrations, protein densities of UCP2 and UCP3 rose, but those of cardiac and skeletal muscle GLUT4 fell. The researchers suggest a possible mechanism linking heart failure with their results. Dr Murray comments: “New treatment to correct these energy defects would be to simultaneously lower plasma free fatty acids and provide an alternative energy source.”

An accompanying commentary (p 1733) by Lionel H Opie (University of Cape Town Medical School, Cape Town, South Africa) questions the investigators’ postulated mechanism: “Although hypothesis-generating, the links between increased plasma free fatty acids and the content of uncoupling proteins do not prove a causative role for the uncoupling proteins, nor that the uncoupling proteins actually waste oxygen in patients with heart failure…The findings should be confirmed for other causes and severities of heart failure.”

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