title: Formation of elongated giant mitochondria in DFO-induced cellular senescence: involvement of enhanced fusion process through modulation of Fis1.
abstract: Enlarged or giant mitochondria have often been documented in aged tissues although their role and underlying mechanism remain unclear. We report here how highly elongated giant mitochondria are formed in and related to the senescent arrest. The mitochondrial morphology was progressively changed to a highly elongated form during deferoxamine (DFO)-induced senescent arrest of Chang cells, accompanied by increase of intracellular ROS level and decrease of mtDNA content. Interestingly, under exposure to subcytotoxic doses of H2O2 (200 microM), about 65% of Chang cells harbored elongated mitochondria with senescent phenotypes whereas ethidium bromide (EtBr) (50 ng/ml) only reformed the cristae structure. Elongated giant mitochondria were also observed in TGF beta1- or H2O2-induced senescent Mv1Lu cells and in old human diploid fibroblasts (HDFs). In all senescent progresses employed in this study Fis1 protein, a mitochondrial fission modulator, was commonly downexpressed. Overexpression of YFP-Fis1 reversed both mitochondrial elongation and appearance of senescent phenotypes induced by DFO, implying its critical involvement in the arrest. Finally, we found that direct induction of mitochondrial elongation by blocking mitochondrial fission process with Fis1-DeltaTM or Drp1-K38A was sufficient to develop senescent phenotypes with increased ROS production. These data suggest that mitochondrial elongation may play an important role as a mediator in stress-induced premature senescence.
authors.affiliation: Department of Biochemistry and Molecular Biology, Ajou University School of Medicine, Suwon, South Korea.
authors.forename: Young-Sil
authors.initials: YS
authors.lastname: Yoon
authors.forename: Dong-Sun
authors.initials: DS
authors.lastname: Yoon
authors.forename: In Kyoung
authors.initials: IK
authors.lastname: Lim
authors.forename: Soo-Han
authors.initials: SH
authors.lastname: Yoon
authors.forename: Hae-Young
authors.initials: HY
authors.lastname: Chung
authors.forename: Manuel
authors.initials: M
authors.lastname: Rojo
authors.forename: Florence
authors.initials: F
authors.lastname: Malka
authors.forename: Mei-Jie
authors.initials: MJ
authors.lastname: Jou
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Martinou
authors.forename: Gyesoon
authors.initials: G
authors.lastname: Yoon
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects*; D002648:Child; D004272:DNA, Mitochondrial / Q000378:metabolism; D003676:Deferoxamine / Q000494:pharmacology*; D004996:Ethidium / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007502:Iron Chelating Agents / Q000494:pharmacology; D008297:Male; D008561:Membrane Fusion / Q000187:drug effects*; D008565:Membrane Proteins; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology* / Q000648:ultrastructure; D051336:Mitochondrial Membranes / Q000187:drug effects; D024101:Mitochondrial Proteins / Q000378:metabolism*; D010641:Phenotype; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D053773:Transforming Growth Factor beta1
chemical_list: D004272:DNA, Mitochondrial; C476525:FIS1 protein, human; D007502:Iron Chelating Agents; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D011993:Recombinant Fusion Proteins; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D006861:Hydrogen Peroxide; D004996:Ethidium; D003676:Deferoxamine