title: Transient mitochondrial DNA double strand breaks in mice cause accelerated aging phenotypes in a ROS-dependent but p53/p21-independent manner.
abstract: We observed that the transient induction of mtDNA double strand breaks (DSBs) in cultured cells led to activation of cell cycle arrest proteins (p21/p53 pathway) and decreased cell growth, mediated through reactive oxygen species (ROS). To investigate this process in vivo we developed a mouse model where we could transiently induce mtDNA DSBs ubiquitously. This transient mtDNA damage in mice caused an accelerated aging phenotype, preferentially affecting proliferating tissues. One of the earliest phenotypes was accelerated thymus shrinkage by apoptosis and differentiation into adipose tissue, mimicking age-related thymic involution. This phenotype was accompanied by increased ROS and activation of cell cycle arrest proteins. Treatment with antioxidants improved the phenotype but the knocking out of p21 or p53 did not. Our results demonstrate that transient mtDNA DSBs can accelerate aging of certain tissues by increasing ROS. Surprisingly, this mtDNA DSB-associated senescence phenotype does not require p21/p53, even if this pathway is activated in the process.
authors.affiliation: Department of Neurology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Milena
authors.identifier: 0000-0001-9202-1527
authors.initials: M
authors.lastname: Pinto
authors.affiliation: Neuroscience Graduate Program, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Alicia M
authors.initials: AM
authors.lastname: Pickrell
authors.affiliation: Graduate Program in Cancer Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Xiao
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Neurology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Sandra R
authors.initials: SR
authors.lastname: Bacman
authors.affiliation: Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Aixin
authors.initials: A
authors.lastname: Yu
authors.affiliation: Department of Neurology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Aline
authors.initials: A
authors.lastname: Hida
authors.affiliation: Department of Cell Biology and Anatomy, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Lloye M
authors.initials: LM
authors.lastname: Dillon
authors.affiliation: Department of Neurosurgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA.|Center for Neuroscience Research, Children's National Medical Center, Washington, DC 20010, USA.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Morton
authors.affiliation: Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Malek
authors.affiliation: Department of Neurology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Siôn L
authors.initials: SL
authors.lastname: Williams
authors.affiliation: Department of Neurology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.|Neuroscience Graduate Program, University of Miami Miller School of Medicine, Miami, FL 33136, USA.|Graduate Program in Cancer Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.|Department of Cell Biology and Anatomy, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Carlos T
authors.initials: CT
authors.lastname: Moraes
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000375:Aging; D000818:Animals; D017209:Apoptosis; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D004272:DNA, Mitochondrial / Q000378:metabolism*; D015252:Deoxyribonucleases, Type II Site-Specific / Q000235:genetics / Q000378:metabolism; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D015735:Mifepristone / Q000633:toxicity; D010641:Phenotype; D017382:Reactive Oxygen Species / Q000378:metabolism; D060168:Thymocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D004272:DNA, Mitochondrial; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D015735:Mifepristone; C024388:CTGCAG-specific type II deoxyribonucleases; D015252:Deoxyribonucleases, Type II Site-Specific; D000111:Acetylcysteine