title: Cardiac mitochondrial energy metabolism in heart failure: Role of cardiolipin and sirtuins.
abstract: Mitochondrial oxidation of fatty acids accounts for the majority of cardiac ATP production in the heart. Fatty acid utilization by cardiac mitochondria is controlled at the level of fatty acid uptake, lipid synthesis, mobilization and mitochondrial import and oxidation. Consequently defective mitochondrial function appears to be central to the development of heart failure. Cardiolipin is a key mitochondrial phospholipid required for the activity of the electron transport chain. In heart failure, loss of cardiolipin and tetralinoleoylcardiolipin helps to fuel the generation of excessive reactive oxygen species that are a by-product of inefficient mitochondrial electron transport chain complexes I and III. In this vicious cycle, reactive oxygen species generate lipid peroxides and may, in turn, cause oxidation of cardiolipin catalyzed by cytochrome c leading to cardiomyocyte apoptosis. Hence, preservation of cardiolipin and mitochondrial function may be keys to the prevention of heart failure development. In this review, we summarize cardiac energy metabolism and the important role that fatty acid uptake and metabolism play in this process and how defects in these result in heart failure. We highlight the key role that cardiolipin and sirtuins play in cardiac mitochondrial β-oxidation. In addition, we review the potential of pharmacological modulation of cardiolipin through the polyphenolic molecule resveratrol as a sirtuin-activator in attenuating mitochondrial dysfunction. Finally, we provide novel experimental evidence that resveratrol treatment increases cardiolipin in isolated H9c2 cardiac myocytes and tetralinoleoylcardiolipin in the heart of the spontaneously hypertensive rat and hypothesize that this leads to improvement in mitochondrial function. This article is part of a Special Issue entitled: Heart Lipid Metabolism edited by G.D. Lopaschuk.
authors.affiliation: Department of Pharmacology & Therapeutics, Faculty of Health Sciences, University of Manitoba, Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) Theme, Children's Hospital Research Institute of Manitoba (CHRIM), Canada.
authors.forename: Vernon W
authors.initials: VW
authors.lastname: Dolinsky
authors.affiliation: Department of Pharmacology & Therapeutics, Faculty of Health Sciences, University of Manitoba, Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) Theme, Children's Hospital Research Institute of Manitoba (CHRIM), Canada.
authors.forename: Laura K
authors.initials: LK
authors.lastname: Cole
authors.affiliation: Department of Medicine, Division of Cardiology, University of Colorado Denver Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: Genevieve C
authors.initials: GC
authors.lastname: Sparagna
authors.affiliation: Department of Pharmacology & Therapeutics, Faculty of Health Sciences, University of Manitoba, Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) Theme, Children's Hospital Research Institute of Manitoba (CHRIM), Canada; Department of Biochemistry and Medical Genetics, Faculty of Health Sciences, Center for Research and Treatment of Atherosclerosis, University of Manitoba, Winnipeg, Manitoba, Canada. Electronic address: ghatch@chrim.ca.
authors.forename: Grant M
authors.initials: GM
authors.lastname: Hatch
mesh_terms: D000818:Animals; D002308:Cardiolipins / Q000378:metabolism*; D004734:Energy Metabolism; D006333:Heart Failure / Q000378:metabolism*; D006801:Humans; D008929:Mitochondria, Heart / Q000378:metabolism*; D010084:Oxidation-Reduction; D037761:Sirtuins / Q000378:metabolism*
chemical_list: D002308:Cardiolipins; D037761:Sirtuins
keywords: Cardiolipin; Heart failure; Mitochondria; Reactive oxygen species; Resveratrol; Sirtuins