title: Resistance of Dynamin-related Protein 1 Oligomers to Disassembly Impairs Mitophagy, Resulting in Myocardial Inflammation and Heart Failure.
abstract: We have reported previously that a missense mutation in the mitochondrial fission gene Dynamin-related protein 1 (Drp1) underlies the Python mouse model of monogenic dilated cardiomyopathy. The aim of this study was to investigate the consequences of the C452F mutation on Drp1 protein function and to define the cellular sequelae leading to heart failure in the Python monogenic dilated cardiomyopathy model. We found that the C452F mutation increased Drp1 GTPase activity. The mutation also conferred resistance to oligomer disassembly by guanine nucleotides and high ionic strength solutions. In a mouse embryonic fibroblast model, Drp1 C452F cells exhibited abnormal mitochondrial morphology and defective mitophagy. Mitochondria in C452F mouse embryonic fibroblasts were depolarized and had reduced calcium uptake with impaired ATP production by oxidative phosphorylation. In the Python heart, we found a corresponding progressive decline in oxidative phosphorylation with age and activation of sterile inflammation. As a corollary, enhancing autophagy by exposure to a prolonged low-protein diet improved cardiac function in Python mice. In conclusion, failure of Drp1 disassembly impairs mitophagy, leading to a downstream cascade of mitochondrial depolarization, aberrant calcium handling, impaired ATP synthesis, and activation of sterile myocardial inflammation, resulting in heart failure.
authors.affiliation: From the Division of Cardiovascular Medicine.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Cahill
authors.affiliation: the Leeds Institute of Molecular Medicine, Wellcome Trust Brenner Building, St. James's University Hospital, Leeds LS9 7TF, United Kingdom.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Leo
authors.affiliation: From the Division of Cardiovascular Medicine.
authors.forename: Matthew
authors.initials: M
authors.lastname: Kelly
authors.affiliation: From the Division of Cardiovascular Medicine.
authors.forename: Alexander
authors.initials: A
authors.lastname: Stockenhuber
authors.affiliation: the Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin;
authors.forename: Nolan W
authors.initials: NW
authors.lastname: Kennedy
authors.affiliation: Weatherall Institute of Molecular Medicine, Nuffield Department of Medicine, and.
authors.forename: Leyuan
authors.initials: L
authors.lastname: Bao
authors.affiliation: the Department of Cell Physiology and Metabolism, University of Geneva, Geneva, CH-1211, Switzerland, and.
authors.forename: Grazia M
authors.initials: GM
authors.lastname: Cereghetti
authors.affiliation: From the Division of Cardiovascular Medicine.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Harper
authors.affiliation: From the Division of Cardiovascular Medicine.
authors.forename: Gabor
authors.initials: G
authors.lastname: Czibik
authors.affiliation: Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Oxford OX3 9DU, United Kingdom;
authors.forename: Chunyan
authors.initials: C
authors.lastname: Liao
authors.affiliation: From the Division of Cardiovascular Medicine.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Bellahcene
authors.affiliation: From the Division of Cardiovascular Medicine.
authors.forename: Violetta
authors.initials: V
authors.lastname: Steeples
authors.affiliation: From the Division of Cardiovascular Medicine.
authors.forename: Safar
authors.initials: S
authors.lastname: Ghaffari
authors.affiliation: From the Division of Cardiovascular Medicine.
authors.forename: Arash
authors.initials: A
authors.lastname: Yavari
authors.affiliation: Weatherall Institute of Molecular Medicine, Nuffield Department of Medicine, and.
authors.forename: Alice
authors.initials: A
authors.lastname: Mayer
authors.affiliation: Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Oxford OX3 9DU, United Kingdom;
authors.forename: Joanna
authors.initials: J
authors.lastname: Poulton
authors.affiliation: Nuffield Division of Clinical Laboratory Sciences and.
authors.forename: David J P
authors.initials: DJ
authors.lastname: Ferguson
authors.affiliation: the Department of Cell Physiology and Metabolism, University of Geneva, Geneva, CH-1211, Switzerland, and.
authors.forename: Luca
authors.initials: L
authors.lastname: Scorrano
authors.affiliation: the Division of Cardiovascular and Diabetes Research, Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds LS2 9JT, United Kingdom.
authors.forename: Nishani T
authors.initials: NT
authors.lastname: Hettiarachchi
authors.affiliation: the Division of Cardiovascular and Diabetes Research, Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds LS2 9JT, United Kingdom.
authors.forename: Chris
authors.initials: C
authors.lastname: Peers
authors.affiliation: the Division of Cardiovascular and Diabetes Research, Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds LS2 9JT, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: Boyle
authors.affiliation: the Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin;
authors.forename: R Blake
authors.initials: RB
authors.lastname: Hill
authors.affiliation: Weatherall Institute of Molecular Medicine, Nuffield Department of Medicine, and.
authors.forename: Alison
authors.initials: A
authors.lastname: Simmons
authors.affiliation: From the Division of Cardiovascular Medicine.
authors.forename: Hugh
authors.initials: H
authors.lastname: Watkins
authors.affiliation: the Leeds Institute of Molecular Medicine, Wellcome Trust Brenner Building, St. James's University Hospital, Leeds LS9 7TF, United Kingdom.
authors.forename: T Neil
authors.initials: TN
authors.lastname: Dear
authors.affiliation: Experimental Therapeutics, Radcliffe Department of Medicine, houman.ashrafian@cardiov.ox.ac.uk.
authors.forename: Houman
authors.initials: H
authors.lastname: Ashrafian
mesh_terms: D000818:Animals; D001704:Biopolymers / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002478:Cells, Cultured; D034281:Dynamins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006333:Heart Failure / Q000209:etiology* / Q000503:physiopathology; D051379:Mice; D063306:Mitophagy; D009154:Mutation; D009205:Myocarditis / Q000209:etiology* / Q000503:physiopathology; D010085:Oxidative Phosphorylation
chemical_list: D001704:Biopolymers; C486391:Dnm1l protein, mouse; D034281:Dynamins
keywords: cardiomyopathy; heart failure; mitochondria; mitochondrial metabolism; mitophagy