title: Mitochondrial hyperfusion induced by loss of the fission protein Drp1 causes ATM-dependent G2/M arrest and aneuploidy through DNA replication stress.
abstract: Mitochondrial fission and fusion cycles are integrated with cell cycle progression. In this paper, we demonstrate that the inhibition of mitochondrial fission protein Drp1 causes an unexpected delay in G2/M cell cycle progression and aneuploidy. In investigating the underlying molecular mechanism, we revealed that inhibiting Drp1 triggers replication stress, which is mediated by a hyperfused mitochondrial structure and unscheduled expression of cyclin E in the G2 phase. This persistent replication stress then induces an ATM-dependent activation of the G2 to M transition cell cycle checkpoint. Knockdown of ATR, an essential kinase in preventing replication stress, significantly enhanced DNA damage and cell death of Drp1-deficienct cells. Persistent mitochondrial hyperfusion also induces centrosomal overamplification and chromosomal instability, which are causes of aneuploidy. Analysis using cells depleted of mitochondrial DNA revealed that these events are not mediated by the defects in mitochondrial ATP production and reactive oxygen species (ROS) generation. Thus dysfunctional mitochondrial fission directly induces genome instability by replication stress, which then initiates the DNA damage response. Our findings provide a novel mechanism that contributes to the cellular dysfunction and diseases associated with altered mitochondrial dynamics.
authors.affiliation: Department of Pharmacology and Chemical Biology, Hillman Cancer Center          Pittsburgh, PA 15213           USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Qian
authors.forename: Serah
authors.initials: S
authors.lastname: Choi
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Gibson
authors.forename: Simon C
authors.initials: SC
authors.lastname: Watkins
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Bakkenist
authors.forename: Bennett
authors.initials: B
authors.lastname: Van Houten
mesh_terms: D000782:Aneuploidy; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D015153:Blotting, Western; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology*; D002455:Cell Division / Q000235:genetics / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004261:DNA Replication / Q000235:genetics / Q000502:physiology*; D034281:Dynamins; D005455:Fluorescent Antibody Technique; D016195:G2 Phase / Q000235:genetics / Q000502:physiology; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000235:genetics / Q000502:physiology; D018613:Microscopy, Confocal; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D013481:Superoxides / Q000378:metabolism
chemical_list: D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D013481:Superoxides; D020558:GTP Phosphohydrolases; C110768:DNM1L protein, human; D034281:Dynamins