title: Decreased expression of Drp1 and Fis1 mediates mitochondrial elongation in senescent cells and enhances resistance to oxidative stress through PINK1.
abstract: Mitochondria display different morphologies, depending on cell type and physiological situation. In many senescent cell types, an extensive elongation of mitochondria occurs, implying that the increase of mitochondrial length in senescence could have a functional role. To test this hypothesis, human endothelial cells (HUVECs) were aged in vitro. Young HUVECs had tubular mitochondria, whereas senescent cells were characterized by long interconnected mitochondria. The change in mitochondrial morphology was caused by downregulation of the expression of Fis1 and Drp1, two proteins regulating mitochondrial fission. Targeted photodamage of mitochondria induced the formation of reactive oxygen species (ROS), which triggered mitochondrial fragmentation and loss of membrane potential in young cells, whereas senescent cells proved to be resistant. Alterations of the Fis1 and Drp1 expression levels also influenced the expression of the putative serine-threonine kinase PINK1, which is associated with the PARK6 variant of Parkinson's disease. Downregulation of PINK1 or overexpression of a PINK1 mutant (G309D) increased the sensitivity against ROS in young cells. These results indicate that there is a Drp1- and Fis1-induced, and PINK1-mediated protection mechanism in senescent cells, which, when compromised, could contribute to the age-related progression of Parkinson's disease and arteriosclerosis.
authors.affiliation: Kinematic Cell Research Group, Institute for Cell Biology and Neuroscience, Center of Excellence Frankfurt: Macromolecular Complexes, Goethe University, Max-von-Laue-Str. 9, 60438 Frankfurt/Main, Germany.
authors.forename: Sören
authors.initials: S
authors.lastname: Mai
authors.forename: Michael
authors.initials: M
authors.lastname: Klinkenberg
authors.forename: Georg
authors.initials: G
authors.lastname: Auburger
authors.forename: Jürgen
authors.initials: J
authors.lastname: Bereiter-Hahn
authors.forename: Marina
authors.initials: M
authors.lastname: Jendrach
mesh_terms: D016922:Cellular Senescence / Q000528:radiation effects; D034281:Dynamins; D042783:Endothelial Cells / Q000166:cytology* / Q000201:enzymology / Q000528:radiation effects; D020558:GTP Phosphohydrolases / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000528:radiation effects; D006801:Humans; D008027:Light; D008565:Membrane Proteins / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D008928:Mitochondria / Q000201:enzymology* / Q000473:pathology / Q000528:radiation effects; D024101:Mitochondrial Proteins / Q000378:metabolism*; D008954:Models, Biological; D018384:Oxidative Stress / Q000528:radiation effects; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D014471:Umbilical Veins / Q000166:cytology; D015854:Up-Regulation / Q000528:radiation effects; D000099202:PTEN-Induced Putative Kinase
chemical_list: D034281:Dynamins; D020558:GTP Phosphohydrolases; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D011494:Protein Kinases; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D000099202:PTEN-Induced Putative Kinase; C476525:FIS1 protein, human; C110768:DNM1L protein, human