Mitochondrial dysfunction in heart failure
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Mitochondrial dysfunction in heart failure Mariana G. Rosca • Charles L. Hoppel
Published online: 5 September 2012 Ó Springer Science+Business Media, LLC 2012
Abstract Heart failure (HF) is a complex chronic clinical syndrome. Energy deficit is considered to be a key contributor to the development of both cardiac and skeletal myopathy. In HF, several components of cardiac and skeletal muscle bioenergetics are altered, such as oxygen availability, substrate oxidation, mitochondrial ATP production, and ATP transfer to the contractile apparatus via the creatine kinase shuttle. This review focuses on alterations in mitochondrial biogenesis and respirasome organization, substrate oxidation coupled with ATP synthesis in the context of their contribution to the chronic energy deficit, and mechanical dysfunction of the cardiac and skeletal muscle in HF. We conclude that HF is associated with decreased mitochondrial biogenesis and function in both heart and skeletal muscle, supporting the concept of a systemic mitochondrial cytopathy. The sites of mitochondrial defects are located within the electron transport and phosphorylation apparatus and differ with the etiology and progression of HF in the two mitochondrial populations (subsarcolemmal and interfibrillar) of cardiac and skeletal muscle. The roles of adrenergic stimulation, the renin–angiotensin system, and cytokines are evaluated as factors responsible for the systemic energy deficit. We propose a cyclic AMP-mediated mechanism by which increased adrenergic stimulation contributes to the mitochondrial dysfunction. Keywords Heart failure Mitochondria Heart Skeletal muscle Oxidative phosphorylation
M. G. Rosca C. L. Hoppel (&) Departments of Medicine and Pharmacology and Center for Mitochondrial Diseases, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106-4981, USA e-mail: [email protected]
Introduction Heart failure (HF) is a complex clinical syndrome characterized by impaired contractile performance of the myocardium leading to inability of the heart to supply adequate amounts of blood to meet the metabolic needs of peripheral tissues. Increased preload and afterload, neurohormonal dysregulation, cardiac ischemia, and intrinsic abnormalities of the myocardium are common etiologic factors of HF. The progression of HF is dictated by changes in major signal transduction pathways, abnormalities of calcium homeostasis and energy fluxes, and alterations of the cardiac contractile apparatus. The impairment of bioenergetics is considered key in the progression of HF. The ATP that the myocardium has to synthesize and transfer to sustain the excitation–contraction coupling must continuously support an optimal myocardial performance in both systolic and diastolic periods. The heart has no excess capacity for energy production over energy utilization since during maximal exercise cardiac muscle uses 90 % of its oxidative capacity. Ninety percent of this requirement is met by mitochondrial oxidative phosphorylation, which
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