title: Acquired deficiency of tafazzin in the adult heart: Impact on mitochondrial function and response to cardiac injury.
abstract: The content and composition of cardiolipin (CL) is critical for preservation of mitochondrial oxidative phosphorylation (OXPHOS) and inner membrane integrity. Tafazzin (Taz) is an enzyme responsible for remodeling of immature CL containing mixed acyl groups into the mature tetralinoleyl form (C18:2)4-CL. We hypothesized that acquired defects in Taz in the mature heart would impact remodeling of CL and augment cardiac injury. The role of acquired Taz deficiency was studied using the inducible Taz knockdown (TazKD) mouse. Taz-specific shRNA is induced by doxycycline (DOX). One day of DOX intake decreased Taz mRNA in the heart to 20% vs. DOX-treated WT. Knockdown was initiated at an adult age and was stable during long term feeding. CL phenotype was assessed by (C18:2)4-CL content and was reduced 40% vs. WT at two months of DOX. TazKD showed increased production of reactive oxygen species and increased susceptibility to permeability transition pore opening at baseline. However, OXPHOS measured using the rate of oxygen consumption was unchanged in the setting of acquired Taz deficiency. Infarct size, measured in isolated buffer-perfused Langendorff hearts following 25min. Stop flow ischemia and 60min. Reperfusion was not altered in TazKD hearts. Thus, impaired Taz-function with onset at adult age does not enhance susceptibility to ischemia-reperfusion injury.
authors.affiliation: Division of Cardiology, Department of Internal Medicine and Pauley Heart Center, United States.
authors.forename: Karol
authors.initials: K
authors.lastname: Szczepanek
authors.affiliation: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298, United States.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Allegood
authors.affiliation: Division of Cardiology, Department of Internal Medicine and Pauley Heart Center, United States.
authors.forename: Hema
authors.initials: H
authors.lastname: Aluri
authors.affiliation: Division of Cardiology, Department of Internal Medicine and Pauley Heart Center, United States.
authors.forename: Ying
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Division of Cardiology, Department of Internal Medicine and Pauley Heart Center, United States.
authors.forename: Qun
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Division of Cardiology, Department of Internal Medicine and Pauley Heart Center, United States; Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298, United States; McGuire Veterans Affairs Medical Center, Richmond, VA 23249, United States. Electronic address: edward.lesnefsky@vcuhealth.org.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Lesnefsky
mesh_terms: D000217:Acyltransferases; D000818:Animals; D002308:Cardiolipins / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation; D055785:Gene Knockdown Techniques; D005838:Genotype; D000067268:Isolated Heart Preparation; D008297:Male; D008822:Mice, Transgenic; D008929:Mitochondria, Heart / Q000378:metabolism* / Q000473:pathology; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D010085:Oxidative Phosphorylation; D010641:Phenotype; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics
chemical_list: D002308:Cardiolipins; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D014157:Transcription Factors; D000217:Acyltransferases; C486363:tafazzin protein, mouse
keywords: Aging; Mitochondria; Myocardial infarction; Oxidative phosphorylation; Permeability transition pore; Reactive oxygen species