Hearts deficient in both Mfn1 and Mfn2 are protected against acute myocardial infarction
Copyright policy )Hearts deficient in both Mfn1 and Mfn2 are protected against acute myocardial infarction
AbstractMitochondria 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 Ca2+-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 Ca2+ 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.
- University College London United Kingdom
- Washington University United States
- Washington University in St. Louis United States
- University of Mary United States
- Washington University in St. Louis School of Medicine United States
heart output, cell organelle, Myocardial Infarction, Antimycin A, Gene Expression, reactive oxygen metabolite, confocal microscopy, Mitochondrial Dynamics, Mitochondrial Membrane Transport Proteins, GTP Phosphohydrolases, heart mitochondrion, Mice, heart infarction size, cytochrome c oxidase, calcium ion, mitofusin 2, echocardiography, mitochondrion, mitofusin 1, animal, genetics, Myocytes, Cardiac, Mice, Knockout, cardiac muscle cell, antimycin A1, guanosine triphosphatase, Mfn1 protein, deficiency, succinate dehydrogenase (ubiquinone), Mitochondria, Sarcoplasmic Reticulum, fractional shortening, priority journal, Original Article, ubiquinol cytochrome c reductase, cardiac muscle, animal experiment, 610, Myocardial Reperfusion Injury, Article, heart protection, disorders of mitochondrial functions, heart left ventricle hypertrophy, reduced nicotinamide adenine dinucleotide dehydrogenase (ubiquinone), Animals, controlled study, protein expression, mouse, calcium, nonhuman, Mitochondrial Permeability Transition Pore, animal model, Myocardium, mitochondrial permeability transition pore, Mfn2 protein, mitochondrial dynamics, myocardial ischemia reperfusion injury, carrier protein, acute heart infarction, drug effects, gene expression, Calcium, knockout mouse, Reactive Oxygen Species, metabolism, mitochondrion swelling
heart output, cell organelle, Myocardial Infarction, Antimycin A, Gene Expression, reactive oxygen metabolite, confocal microscopy, Mitochondrial Dynamics, Mitochondrial Membrane Transport Proteins, GTP Phosphohydrolases, heart mitochondrion, Mice, heart infarction size, cytochrome c oxidase, calcium ion, mitofusin 2, echocardiography, mitochondrion, mitofusin 1, animal, genetics, Myocytes, Cardiac, Mice, Knockout, cardiac muscle cell, antimycin A1, guanosine triphosphatase, Mfn1 protein, deficiency, succinate dehydrogenase (ubiquinone), Mitochondria, Sarcoplasmic Reticulum, fractional shortening, priority journal, Original Article, ubiquinol cytochrome c reductase, cardiac muscle, animal experiment, 610, Myocardial Reperfusion Injury, Article, heart protection, disorders of mitochondrial functions, heart left ventricle hypertrophy, reduced nicotinamide adenine dinucleotide dehydrogenase (ubiquinone), Animals, controlled study, protein expression, mouse, calcium, nonhuman, Mitochondrial Permeability Transition Pore, animal model, Myocardium, mitochondrial permeability transition pore, Mfn2 protein, mitochondrial dynamics, myocardial ischemia reperfusion injury, carrier protein, acute heart infarction, drug effects, gene expression, Calcium, knockout mouse, Reactive Oxygen Species, metabolism, mitochondrion swelling
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