title: Pim-1 preserves mitochondrial morphology by inhibiting dynamin-related protein 1 translocation.
abstract: Mitochondrial morphological dynamics affect the outcome of ischemic heart damage and pathogenesis. Recently, mitochondrial fission protein dynamin-related protein 1 (Drp1) has been identified as a mediator of mitochondrial morphological changes and cell death during cardiac ischemic injury. In this study, we report a unique relationship between Pim-1 activity and Drp1 regulation of mitochondrial morphology in cardiomyocytes challenged by ischemic stress. Transgenic hearts overexpressing cardiac Pim-1 display reduction of total Drp1 protein levels, increased phosphorylation of Drp1-(S637), and inhibition of Drp1 localization to the mitochondria. Consistent with these findings, adenoviral-induced Pim-1 neonatal rat cardiomyocytes (NRCMs) retain a reticular mitochondrial phenotype after simulated ischemia (sI) and decreased Drp1 mitochondrial sequestration. Interestingly, adenovirus Pim-dominant negative NRCMs show increased expression of Bcl-2 homology 3 (BH3)-only protein p53 up-regulated modulator of apoptosis (PUMA), which has been previously shown to induce Drp1 accumulation at mitochondria and increase sensitivity to apoptotic stimuli. Overexpression of the p53 up-regulated modulator of apoptosis-dominant negative adenovirus attenuates localization of Drp1 to mitochondria in adenovirus Pim-dominant negative NRCMs promotes reticular mitochondrial morphology and inhibits cell death during sI. Therefore, Pim-1 activity prevents Drp1 compartmentalization to the mitochondria and preserves reticular mitochondrial morphology in response to sI.
authors.affiliation: San Diego State Heart Institute, San Diego State University, San Diego, CA 92182, USA.
authors.forename: Shabana
authors.initials: S
authors.lastname: Din
authors.forename: Matthew
authors.initials: M
authors.lastname: Mason
authors.forename: Mirko
authors.initials: M
authors.lastname: Völkers
authors.forename: Bevan
authors.initials: B
authors.lastname: Johnson
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Cottage
authors.forename: Zeping
authors.initials: Z
authors.lastname: Wang
authors.forename: Anya Y
authors.initials: AY
authors.lastname: Joyo
authors.forename: Pearl
authors.initials: P
authors.lastname: Quijada
authors.forename: Peter
authors.initials: P
authors.lastname: Erhardt
authors.forename: Nancy S
authors.initials: NS
authors.lastname: Magnuson
authors.forename: Mathias H
authors.initials: MH
authors.lastname: Konstandin
authors.forename: Mark A
authors.initials: MA
authors.lastname: Sussman
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D034281:Dynamins / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology; D010766:Phosphorylation; D021381:Protein Transport; D051573:Proto-Oncogene Proteins c-pim-1 / Q000378:metabolism / Q000502:physiology*; D051381:Rats
chemical_list: C496636:Pim1 protein, mouse; C496637:Pim1 protein, rat; D051573:Proto-Oncogene Proteins c-pim-1; C486391:Dnm1l protein, mouse; C519851:Dnm1l protein, rat; D034281:Dynamins