title: Transgenic overexpression of mitofilin attenuates diabetes mellitus-associated cardiac and mitochondria dysfunction.
abstract: Mitofilin, also known as heart muscle protein, is an inner mitochondrial membrane structural protein that plays a central role in maintaining cristae morphology and structure. It is a critical component of the mitochondrial contact site and cristae organizing system (MICOS) complex which is important for mitochondrial architecture and cristae morphology. Our laboratory has previously reported alterations in mitochondrial morphology and proteomic make-up during type 1 diabetes mellitus, with mitofilin being significantly down-regulated in interfibrillar mitochondria (IFM). The goal of this study was to investigate whether overexpression of mitofilin can limit mitochondrial disruption associated with the diabetic heart through restoration of mitochondrial morphology and function. A transgenic mouse line overexpressing mitofilin was generated and mice injected intraperitoneally with streptozotocin using a multi low-dose approach. Five weeks following diabetes mellitus onset, cardiac contractile function was assessed. Restoration of ejection fraction and fractional shortening was observed in mitofilin diabetic mice as compared to wild-type controls (P<0.05 for both). Decrements observed in electron transport chain (ETC) complex I, III, IV and V activities, state 3 respiration, lipid peroxidation as well as mitochondria membrane potential in type 1 diabetic IFM were restored in mitofilin diabetic mice (P<0.05 for all). Qualitative analyses of electron micrographs revealed restoration of mitochondrial cristae structure in mitofilin diabetic mice as compared to wild-type controls. Furthermore, measurement of mitochondrial internal complexity using flow cytometry displayed significant reduction in internal complexity in diabetic IFM which was restored in mitofilin diabetic IFM (P<0.05). Taken together these results suggest that transgenic overexpression of mitofilin preserves mitochondrial structure, leading to restoration of mitochondrial function and attenuation of cardiac contractile dysfunction in the diabetic heart.
authors.affiliation: West Virginia University School of Medicine, Division of Exercise Physiology, Center for Cardiovascular and Respiratory Sciences, Morgantown, WV 26506, USA.
authors.forename: Dharendra
authors.initials: D
authors.lastname: Thapa
authors.affiliation: West Virginia University School of Medicine, Division of Exercise Physiology, Center for Cardiovascular and Respiratory Sciences, Morgantown, WV 26506, USA.
authors.forename: Cody E
authors.initials: CE
authors.lastname: Nichols
authors.affiliation: West Virginia University School of Medicine, Division of Exercise Physiology, Center for Cardiovascular and Respiratory Sciences, Morgantown, WV 26506, USA.
authors.forename: Sara E
authors.initials: SE
authors.lastname: Lewis
authors.affiliation: West Virginia University School of Medicine, Division of Exercise Physiology, Center for Cardiovascular and Respiratory Sciences, Morgantown, WV 26506, USA.
authors.forename: Danielle L
authors.initials: DL
authors.lastname: Shepherd
authors.affiliation: West Virginia University School of Medicine, Division of Exercise Physiology, Center for Cardiovascular and Respiratory Sciences, Morgantown, WV 26506, USA.
authors.forename: Rajaganapathi
authors.initials: R
authors.lastname: Jagannathan
authors.affiliation: West Virginia University School of Medicine, Division of Exercise Physiology, Center for Cardiovascular and Respiratory Sciences, Morgantown, WV 26506, USA.
authors.forename: Tara L
authors.initials: TL
authors.lastname: Croston
authors.affiliation: West Virginia University School of Medicine, Department of Surgery, Morgantown, WV 26506, USA.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Tveter
authors.affiliation: West Virginia University School of Medicine, Department of Surgery, Morgantown, WV 26506, USA.
authors.forename: Anthony A
authors.initials: AA
authors.lastname: Holden
authors.affiliation: West Virginia University School of Medicine, Division of Exercise Physiology, Center for Cardiovascular and Respiratory Sciences, Morgantown, WV 26506, USA.
authors.forename: Walter A
authors.initials: WA
authors.lastname: Baseler
authors.affiliation: West Virginia University School of Medicine, Division of Exercise Physiology, Center for Cardiovascular and Respiratory Sciences, Morgantown, WV 26506, USA. Electronic address: jhollander@hsc.wvu.edu.
authors.forename: John M
authors.initials: JM
authors.lastname: Hollander
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001835:Body Weight; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D004579:Electron Transport; D006321:Heart / Q000503:physiopathology*; D006801:Humans; D015227:Lipid Peroxidation; D008297:Male; D053078:Membrane Potential, Mitochondrial; D008822:Mice, Transgenic; D008929:Mitochondria, Heart / Q000378:metabolism* / Q000648:ultrastructure; D063154:Mitochondrial Dynamics; D024101:Mitochondrial Proteins / Q000378:metabolism*; D009124:Muscle Proteins / Q000378:metabolism*; D009200:Myocardial Contraction; D063347:Native Polyacrylamide Gel Electrophoresis; D009929:Organ Size; D018384:Oxidative Stress
chemical_list: C088548:IMMT protein, human; D024101:Mitochondrial Proteins; D009124:Muscle Proteins
keywords: Diabetes mellitus; Electron transport chain; Mitochondria; Mitofilin