Inhibiting Mitochondrial Fission Protects the Heart Against Ischemia/Reperfusion Injury

• Published in: Circulation (New York, N.Y.) Vol. 121; no. 18; pp. 2012 - 2022
• Main Authors: ONG, Sang-Bing, SUBRAYAN, Sapna, LIM, Shiang Y, YELLON, Derek M, DAVIDSON, Sean M, HAUSENLOY, Derek J
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 11.05.2010
• Subjects: Age Factors; Animals; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cardiotonic Agents - pharmacology; Cardiovascular system; Cell Death - physiology; Cell Line; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Dynamins; Green Fluorescent Proteins - genetics; GTP Phosphohydrolases - antagonists & inhibitors; GTP Phosphohydrolases - genetics; GTP Phosphohydrolases - metabolism; Male; Medical sciences; Membrane Fusion - physiology; Mice; Mice, Inbred C57BL; Microscopy, Confocal; Microscopy, Electron; Microtubule-Associated Proteins - antagonists & inhibitors; Microtubule-Associated Proteins - genetics; Microtubule-Associated Proteins - metabolism; Mitochondria - drug effects; Mitochondria - physiology; Mitochondria - ultrastructure; Mitochondrial Membranes - drug effects; Mitochondrial Membranes - physiology; Mitochondrial Membranes - ultrastructure; Myocardial Reperfusion Injury - drug therapy; Myocardial Reperfusion Injury - pathology; Myocardial Reperfusion Injury - physiopathology; Myocytes, Cardiac - cytology; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - physiology; Pharmacology. Drug treatments; Quinazolinones - pharmacology; Transfection; Vasodilator agents. Cerebral vasodilators; Vascular disease; Myocardial infarction; cardiomyocytes; Oxygen; Reperfusion; Ischemia reperfusion; Hypoxia; Myocardial ischemia; Cardiovascular disease; Coronary heart disease; Myocardial disease; ischemia
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/circulationaha.109.906610

Whether alterations in mitochondrial morphology affect the susceptibility of the heart to ischemia/reperfusion injury is unknown. We hypothesized that modulating mitochondrial morphology protects the heart against ischemia/reperfusion injury. In response to ischemia, mitochondria in HL-1 cells (a cardiac-derived cell line) undergo fragmentation, a process that is dependent on the mitochondrial fission protein dynamin-related protein 1 (Drp1). Transfection of HL-1 cells with the mitochondrial fusion proteins mitofusin 1 or 2 or with Drp1(K38A), a dominant-negative mutant form of Drp1, increased the percentage of cells containing elongated mitochondria (65+/-4%, 69+/-5%, and 63+/-6%, respectively, versus 46+/-6% in control: n=80 cells per group; P<0.05), decreased mitochondrial permeability transition pore sensitivity (by 2.4+/-0.5-, 2.3+/-0.7-, and 2.4+/-0.3-fold, respectively; n=80 cells per group; P<0.05), and reduced cell death after simulated ischemia/reperfusion injury (11.6+/-3.9%, 16.2+/-3.9%, and 12.1+/-2.9%, respectively, versus 41.8+/-4.1% in control: n=320 cells per group; P<0.05). Treatment of HL-1 cells with mitochondrial division inhibitor-1, a pharmacological inhibitor of Drp1, replicated these beneficial effects. Interestingly, elongated interfibrillar mitochondria were identified in the adult rodent heart with confocal and electron microscopy, and in vivo treatment with mitochondrial division inhibitor-1 increased the percentage of elongated mitochondria from 3.6+/-0.5% to 14.5+/-2.8% (P=0.023). Finally, treatment of adult murine cardiomyocytes with mitochondrial division inhibitor-1 reduced cell death and inhibited mitochondrial permeability transition pore opening after simulated ischemia/reperfusion injury, and in vivo treatment with mitochondrial division inhibitor-1 reduced myocardial infarct size in mice subject to coronary artery occlusion and reperfusion (21.0+/-2.2% with mitochondrial division inhibitor-1 versus 48.0+/-4.5% in control; n=6 animals per group; P<0.05). Inhibiting mitochondrial fission protects the heart against ischemia/reperfusion injury, suggesting a novel pharmacological strategy for cardioprotection.