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Mitochondrial hyperfusion induced by loss of the fission protein Drp1 causes ATM-dependent G2/M arrest and aneuploidy through DNA replication stress
Wei Qian, Serah Choi, Gregory A. Gibson, Simon C. Watkins, Christopher J. Bakkenist, Bennett Van Houten


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.


  • Funding

    This work was funded, in part, by a grant with the Pennsylvania Department of Health, PA CURE. This work was also supported by funding from the National Insitutes of Health [grant numbers R01CA148644 to C.J.B., P30CA047904, P50CA097190, P50CA121973]. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. Deposited in PMC for release after 12 months.

  • Supplementary material available online at

  • Accepted September 10, 2012.
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