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Distinct mitochondrial retrograde signals control the G1-S cell cycle checkpoint

Nature Genetics volume 40, pages 356–361 (2008)Cite this article

Abstract

During electron transport, the mitochondrion generates ATP and reactive oxygen species (ROS), a group of partially reduced and highly reactive metabolites of oxygen1. In this in vivo genetic analysis in Drosophila melanogaster, we establish that disruption of complex I of the mitochondrial electron transport chain specifically retards the cell cycle during the G1-S transition. The mechanism involves a specific signaling cascade initiated by ROS and transduced by ASK-1, JNK, FOXO and the Drosophila p27 homolog, Dacapo. On the basis of our data combined with previous analyses of the system2, we conclude that mitochondrial dysfunction activates at least two retrograde signals to specifically enforce a G1-S cell cycle checkpoint. One such signal involves an increase in AMP production and downregulation of cyclin E protein; another independent pathway involves increased ROS and upregulation of Dacapo. Thus, our results indicate that the mitochondrion can use AMP and ROS at sublethal concentrations as independent signaling molecules to modulate cell cycle progression.

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Figure 1: Mutations in genes encoding mitochondrial proteins affect cell cycle progression.
Figure 2: The p27 homolog, Dacapo is upregulated in Pdsw mutant cells.
Figure 3: Scavenging ROS rescues the proliferative defect of Pdsw mutant cells.
Figure 4: ROS activates the JNK pathway to arrest Pdsw mutant cells in S phase.

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Acknowledgements

We thank A. Courey for his help with cell-line experiments and members of the Banerjee laboratory for comments on the manuscript. We deeply appreciate S. Ghosh's assistance with cell counting. We are indebted to Y.N. Jan (University of California San Francisco), T. Kojima (University of Tokyo), T. Orr-Weaver (Massachusetts Institute of Technology), H. Richardson (Peter MacCallum Cancer Institute Australia), W. Du (University of Chicago), I. Hariharan (University of Califonia Berkeley), R. Holmgren (Northwestern University), B. Edgar (Fred Hutchinson Cancer Research Center), B. Hay (Caltech) and the Iowa Hybridoma Center for antibodies and to B. Dickson (Research Institute of Molecular Pathology, Vienna), C. Lehner (University of Zurich), E. Hafen (Swiss Federal Institute of Technology, Zurich), F. Missirlis (University of London), M. Miura (University of Tokyo), A. Martinez-Arias (University of Cambridge) and the Bloomington Stock Center for fly stocks. We thank J. Chen, G. Call and members of the University of California Los Angeles undergraduate consortium for initial identification of the Pdsw mutant. We acknowledge the Jonsson Comprehensive Cancer Center FACS analysis core for their help in flow cytometry. This study was supported by US National Institutes of Health grant R01-EY00852 to U.B.

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Authors and Affiliations

  1. Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, 90095, California, USA

    Edward Owusu-Ansah, Amir Yavari, Sudip Mandal & Utpal Banerjee

  2. Molecular Biology Institute, University of California, Los Angeles, Los Angeles, 90095, California, USA

    Utpal Banerjee

  3. Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, 90095, California, USA

    Utpal Banerjee

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  1. Edward Owusu-Ansah
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Correspondence to Utpal Banerjee.

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Owusu-Ansah, E., Yavari, A., Mandal, S. et al. Distinct mitochondrial retrograde signals control the G1-S cell cycle checkpoint. Nat Genet 40, 356–361 (2008). https://doi.org/10.1038/ng.2007.50

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