title: Hearts deficient in both Mfn1 and Mfn2 are protected against acute myocardial infarction.
abstract: Mitochondria alter their shape by undergoing cycles of fusion and fission. Changes in mitochondrial morphology impact on the cellular response to stress, and their interactions with other organelles such as the sarcoplasmic reticulum (SR). Inhibiting mitochondrial fission can protect the heart against acute ischemia/reperfusion (I/R) injury. However, the role of the mitochondrial fusion proteins, Mfn1 and Mfn2, in the response of the adult heart to acute I/R injury is not clear, and is investigated in this study. To determine the effect of combined Mfn1/Mfn2 ablation on the susceptibility to acute myocardial I/R injury, cardiac-specific ablation of both Mfn1 and Mfn2 (DKO) was initiated in mice aged 4-6 weeks, leading to knockout of both these proteins in 8-10-week-old animals. This resulted in fragmented mitochondria (electron microscopy), decreased mitochondrial respiratory function (respirometry), and impaired myocardial contractile function (echocardiography). In DKO mice subjected to in vivo regional myocardial ischemia (30 min) followed by 24 h reperfusion, myocardial infarct size (IS, expressed as a % of the area-at-risk) was reduced by 46% compared with wild-type (WT) hearts. In addition, mitochondria from DKO animals had decreased MPTP opening susceptibility (assessed by Ca(2+)-induced mitochondrial swelling), compared with WT hearts. Mfn2 is a key mediator of mitochondrial/SR tethering, and accordingly, the loss of Mfn2 in DKO hearts reduced the number of interactions measured between these organelles (quantified by proximal ligation assay), attenuated mitochondrial calcium overload (Rhod2 confocal microscopy), and decreased reactive oxygen species production (DCF confocal microscopy) in response to acute I/R injury. No differences in isolated mitochondrial ROS emissions (Amplex Red) were detected in response to Ca(2+) and Antimycin A, further implicating disruption of mitochondria/SR tethering as the protective mechanism. In summary, despite apparent mitochondrial dysfunction, hearts deficient in both Mfn1 and Mfn2 are protected against acute myocardial infarction due to impaired mitochondria/SR tethering.
authors.affiliation: The Hatter Cardiovascular Institute, University College London, London, UK.
authors.forename: A R
authors.initials: AR
authors.lastname: Hall
authors.affiliation: The Hatter Cardiovascular Institute, University College London, London, UK.
authors.forename: N
authors.initials: N
authors.lastname: Burke
authors.affiliation: The Hatter Cardiovascular Institute, University College London, London, UK.
authors.forename: R K
authors.initials: RK
authors.lastname: Dongworth
authors.affiliation: The Hatter Cardiovascular Institute, University College London, London, UK.
authors.forename: S B
authors.initials: SB
authors.lastname: Kalkhoran
authors.affiliation: Division of Medicine, University College London, London, UK.
authors.forename: A
authors.initials: A
authors.lastname: Dyson
authors.affiliation: The Hatter Cardiovascular Institute, University College London, London, UK.
authors.forename: J M
authors.initials: JM
authors.lastname: Vicencio
authors.affiliation: Center for Pharmacogenomics, Department of Internal Medicine, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: G W
authors.initials: GW
authors.lastname: Dorn
authors.affiliation: The Hatter Cardiovascular Institute, University College London, London, UK.
authors.forename: D M
authors.initials: DM
authors.lastname: Yellon
authors.affiliation: The Hatter Cardiovascular Institute, University College London, London, UK.|Cardiovascular and Metabolic Disorders Program, Duke-National University Singapore Graduate Medical School, Singapore, Singapore.|National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore, Singapore.
authors.forename: D J
authors.initials: DJ
authors.lastname: Hausenloy
mesh_terms: D000818:Animals; D000968:Antimycin A / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D020558:GTP Phosphohydrolases / Q000172:deficiency / Q000235:genetics*; D015870:Gene Expression; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D063154:Mitochondrial Dynamics / Q000187:drug effects; D033681:Mitochondrial Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D009203:Myocardial Infarction / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D015428:Myocardial Reperfusion Injury / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism
chemical_list: D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D017382:Reactive Oxygen Species; D000968:Antimycin A; D020558:GTP Phosphohydrolases; C488750:Mfn1 protein, mouse; C488751:Mfn2 protein, mouse; D002118:Calcium