title: Translational Regulation of the Mitochondrial Genome Following Redistribution of Mitochondrial MicroRNA in the Diabetic Heart.
abstract: BACKGROUND
  Cardiomyocytes are rich in mitochondria which are situated in spatially distinct subcellular regions, including those under the plasma membrane, subsarcolemmal mitochondria, and those between the myofibrils, interfibrillar mitochondria. We previously observed subpopulation-specific differences in mitochondrial proteomes following diabetic insult. The objective of this study was to determine whether mitochondrial genome-encoded proteins are regulated by microRNAs inside the mitochondrion and whether subcellular spatial location or diabetes mellitus influences the dynamics.
  
  
  RESULTS
  Using microarray technology coupled with cross-linking immunoprecipitation and next generation sequencing, we identified a pool of mitochondrial microRNAs, termed mitomiRs, that are redistributed in spatially distinct mitochondrial subpopulations in an inverse manner following diabetic insult. Redistributed mitomiRs displayed distinct interactions with the mitochondrial genome requiring specific stoichiometric associations with RNA-induced silencing complex constituents argonaute-2 (Ago2) and fragile X mental retardation-related protein 1 (FXR1) for translational regulation. In the presence of Ago2 and FXR1, redistribution of mitomiR-378 to the interfibrillar mitochondria following diabetic insult led to downregulation of mitochondrially encoded F0 component ATP6. Next generation sequencing analyses identified specific transcriptome and mitomiR sequences associated with ATP6 regulation. Overexpression of mitomiR-378 in HL-1 cells resulted in its accumulation in the mitochondrion and downregulation of functional ATP6 protein, whereas antagomir blockade restored functional ATP6 protein and cardiac pump function.
  
  
  CONCLUSIONS
  We propose mitomiRs can translationally regulate mitochondrially encoded proteins in spatially distinct mitochondrial subpopulations during diabetes mellitus. The results reveal the requirement of RNA-induced silencing complex constituents in the mitochondrion for functional mitomiR translational regulation and provide a connecting link between diabetic insult and ATP synthase function.
authors.affiliation: From the Department of Human Performances, Division of Exercise Physiology (R.J., D.T., C.E.N., D.L.S., J.C.S., T.L.C., W.A.B., S.E.L., J.M.H.), Center for Cardiovascular and Respiratory Sciences (R.J., D.T., C.E.N., D.L.S., T.L.C., W.A.B., S.E.L., J.M.H.), Department of Microbiology, Immunology and Cell Biology (I.M.), and Mary Babb Randolph Cancer Center (I.M.), West Virginia University School of Medicine, Morgantown.
authors.forename: Rajaganapathi
authors.initials: R
authors.lastname: Jagannathan
authors.affiliation: From the Department of Human Performances, Division of Exercise Physiology (R.J., D.T., C.E.N., D.L.S., J.C.S., T.L.C., W.A.B., S.E.L., J.M.H.), Center for Cardiovascular and Respiratory Sciences (R.J., D.T., C.E.N., D.L.S., T.L.C., W.A.B., S.E.L., J.M.H.), Department of Microbiology, Immunology and Cell Biology (I.M.), and Mary Babb Randolph Cancer Center (I.M.), West Virginia University School of Medicine, Morgantown.
authors.forename: Dharendra
authors.initials: D
authors.lastname: Thapa
authors.affiliation: From the Department of Human Performances, Division of Exercise Physiology (R.J., D.T., C.E.N., D.L.S., J.C.S., T.L.C., W.A.B., S.E.L., J.M.H.), Center for Cardiovascular and Respiratory Sciences (R.J., D.T., C.E.N., D.L.S., T.L.C., W.A.B., S.E.L., J.M.H.), Department of Microbiology, Immunology and Cell Biology (I.M.), and Mary Babb Randolph Cancer Center (I.M.), West Virginia University School of Medicine, Morgantown.
authors.forename: Cody E
authors.initials: CE
authors.lastname: Nichols
authors.affiliation: From the Department of Human Performances, Division of Exercise Physiology (R.J., D.T., C.E.N., D.L.S., J.C.S., T.L.C., W.A.B., S.E.L., J.M.H.), Center for Cardiovascular and Respiratory Sciences (R.J., D.T., C.E.N., D.L.S., T.L.C., W.A.B., S.E.L., J.M.H.), Department of Microbiology, Immunology and Cell Biology (I.M.), and Mary Babb Randolph Cancer Center (I.M.), West Virginia University School of Medicine, Morgantown.
authors.forename: Danielle L
authors.initials: DL
authors.lastname: Shepherd
authors.affiliation: From the Department of Human Performances, Division of Exercise Physiology (R.J., D.T., C.E.N., D.L.S., J.C.S., T.L.C., W.A.B., S.E.L., J.M.H.), Center for Cardiovascular and Respiratory Sciences (R.J., D.T., C.E.N., D.L.S., T.L.C., W.A.B., S.E.L., J.M.H.), Department of Microbiology, Immunology and Cell Biology (I.M.), and Mary Babb Randolph Cancer Center (I.M.), West Virginia University School of Medicine, Morgantown.
authors.forename: Janelle C
authors.initials: JC
authors.lastname: Stricker
authors.affiliation: From the Department of Human Performances, Division of Exercise Physiology (R.J., D.T., C.E.N., D.L.S., J.C.S., T.L.C., W.A.B., S.E.L., J.M.H.), Center for Cardiovascular and Respiratory Sciences (R.J., D.T., C.E.N., D.L.S., T.L.C., W.A.B., S.E.L., J.M.H.), Department of Microbiology, Immunology and Cell Biology (I.M.), and Mary Babb Randolph Cancer Center (I.M.), West Virginia University School of Medicine, Morgantown.
authors.forename: Tara L
authors.initials: TL
authors.lastname: Croston
authors.affiliation: From the Department of Human Performances, Division of Exercise Physiology (R.J., D.T., C.E.N., D.L.S., J.C.S., T.L.C., W.A.B., S.E.L., J.M.H.), Center for Cardiovascular and Respiratory Sciences (R.J., D.T., C.E.N., D.L.S., T.L.C., W.A.B., S.E.L., J.M.H.), Department of Microbiology, Immunology and Cell Biology (I.M.), and Mary Babb Randolph Cancer Center (I.M.), West Virginia University School of Medicine, Morgantown.
authors.forename: Walter A
authors.initials: WA
authors.lastname: Baseler
authors.affiliation: From the Department of Human Performances, Division of Exercise Physiology (R.J., D.T., C.E.N., D.L.S., J.C.S., T.L.C., W.A.B., S.E.L., J.M.H.), Center for Cardiovascular and Respiratory Sciences (R.J., D.T., C.E.N., D.L.S., T.L.C., W.A.B., S.E.L., J.M.H.), Department of Microbiology, Immunology and Cell Biology (I.M.), and Mary Babb Randolph Cancer Center (I.M.), West Virginia University School of Medicine, Morgantown.
authors.forename: Sara E
authors.initials: SE
authors.lastname: Lewis
authors.affiliation: From the Department of Human Performances, Division of Exercise Physiology (R.J., D.T., C.E.N., D.L.S., J.C.S., T.L.C., W.A.B., S.E.L., J.M.H.), Center for Cardiovascular and Respiratory Sciences (R.J., D.T., C.E.N., D.L.S., T.L.C., W.A.B., S.E.L., J.M.H.), Department of Microbiology, Immunology and Cell Biology (I.M.), and Mary Babb Randolph Cancer Center (I.M.), West Virginia University School of Medicine, Morgantown.
authors.forename: Ivan
authors.initials: I
authors.lastname: Martinez
authors.affiliation: From the Department of Human Performances, Division of Exercise Physiology (R.J., D.T., C.E.N., D.L.S., J.C.S., T.L.C., W.A.B., S.E.L., J.M.H.), Center for Cardiovascular and Respiratory Sciences (R.J., D.T., C.E.N., D.L.S., T.L.C., W.A.B., S.E.L., J.M.H.), Department of Microbiology, Immunology and Cell Biology (I.M.), and Mary Babb Randolph Cancer Center (I.M.), West Virginia University School of Medicine, Morgantown. jhollander@hsc.wvu.edu.
authors.forename: John M
authors.initials: JM
authors.lastname: Hollander
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000473:pathology; D058065:Diabetic Cardiomyopathies / Q000378:metabolism* / Q000473:pathology; D054629:Genome, Mitochondrial; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D008929:Mitochondria, Heart / Q000378:metabolism* / Q000473:pathology; D024101:Mitochondrial Proteins; D014176:Protein Biosynthesis; D012313:RNA / Q000378:metabolism*; D000077278:RNA, Mitochondrial
chemical_list: D035683:MicroRNAs; D024101:Mitochondrial Proteins; D000077278:RNA, Mitochondrial; D012313:RNA
keywords: cardiac; diabetes mellitus; genome; microRNAs; mitochondria; mitochondrial; myocytes