title: Dissociation of mitochondrial from sarcoplasmic reticular stress in Drosophila cardiomyopathy induced by molecularly distinct mitochondrial fusion defects.
abstract: Mitochondrial dynamism (fusion and fission) is responsible for remodeling interconnected mitochondrial networks in some cell types. Adult cardiac myocytes lack mitochondrial networks, and their mitochondria are inherently "fragmented". Mitochondrial fusion/fission is so infrequent in cardiomyocytes as to not be observable under normal conditions, suggesting that mitochondrial dynamism may be dispensable in this cell type. However, we previously observed that cardiomyocyte-specific genetic suppression of mitochondrial fusion factors optic atrophy 1 (Opa1) and mitofusin/MARF evokes cardiomyopathy in Drosophila hearts. We posited that fusion-mediated remodeling of mitochondria may be critical for cardiac homeostasis, although never directly observed. Alternately, we considered that inner membrane Opa1 and outer membrane mitofusin/MARF might have other as-yet poorly described roles that affect mitochondrial and cardiac function. Here we compared heart tube function in three models of mitochondrial fragmentation in Drosophila cardiomyocytes: Drp1 expression, Opa1 RNAi, and mitofusin MARF RNA1. Mitochondrial fragmentation evoked by enhanced Drp1-mediated fission did not adversely impact heart tube function. In contrast, RNAi-mediated suppression of either Opa1 or mitofusin/MARF induced cardiac dysfunction associated with mitochondrial depolarization and ROS production. Inhibiting ROS by overexpressing superoxide dismutase (SOD) or suppressing ROMO1 prevented mitochondrial and heart tube dysfunction provoked by Opa1 RNAi, but not by mitofusin/MARF RNAi. In contrast, enhancing the ability of endoplasmic/sarcoplasmic reticulum to handle stress by expressing Xbp1 rescued the cardiomyopathy of mitofusin/MARF insufficiency without improving that caused by Opa1 deficiency. We conclude that decreased mitochondrial size is not inherently detrimental to cardiomyocytes. Rather, preservation of mitochondrial function by Opa1 located on the inner mitochondrial membrane, and prevention of ER stress by mitofusin/MARF located on the outer mitochondrial membrane, are central functions of these "mitochondrial fusion proteins".
authors.affiliation: Center for Pharmacogenomics, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Poonam
authors.initials: P
authors.lastname: Bhandari
authors.affiliation: Center for Pharmacogenomics, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Moshi
authors.initials: M
authors.lastname: Song
authors.affiliation: Center for Pharmacogenomics, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA. Electronic address: gdorn@dom.wustl.edu.
authors.forename: Gerald W
authors.initials: GW
authors.lastname: Dorn
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D009202:Cardiomyopathies / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D003598:Cytoskeletal Proteins / Q000235:genetics; D004195:Disease Models, Animal; D004330:Drosophila; D029721:Drosophila Proteins / Q000172:deficiency / Q000235:genetics; D059865:Endoplasmic Reticulum Stress / Q000235:genetics; D005260:Female; D019204:GTP-Binding Proteins / Q000235:genetics; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D063154:Mitochondrial Dynamics / Q000235:genetics; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D009928:Organ Specificity / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1; D000099156:Superoxide Dismutase 2
chemical_list: D003598:Cytoskeletal Proteins; D029721:Drosophila Proteins; D019204:GTP-Binding Proteins; D008565:Membrane Proteins; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D000099156:Superoxide Dismutase 2; C527117:Marf protein, Drosophila; C527116:OPA1 protein, Drosophila; C504426:DRP1 protein, Drosophila
keywords: Drosophila; Endoplasmic reticular stress; Mitochondrial fusion; Mitofusin; Optic Atrophy 1; Reactive oxygen species