Distinct mitochondrial retrograde signals control the G1-S cell cycle checkpoint.
During electron transport, the mitochondrion generates ATP and reactive oxygen species (ROS), a group of partially reduced and highly reactive metabolites of oxygen. 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 system, 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.
Owusu-Ansah
Edward
E
Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, California 90095, USA.
Yavari
Amir
A
Mandal
Sudip
S
Banerjee
Utpal
U
D000249:Adenosine Monophosphate / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D030801:Animals, Genetically Modified; D002453:Cell Cycle / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D029721:Drosophila Proteins / Q000235:genetics; D004331:Drosophila melanogaster; D042967:Electron Transport Complex I / Q000235:genetics; D025461:Feedback, Physiological / Q000502:physiology; D016193:G1 Phase / Q000235:genetics; D050259:Genes, Mitochondrial; D007908:Lens, Crystalline / Q000378:metabolism; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D008954:Models, Biological; D009687:Nuclear Proteins / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism / Q000494:pharmacology*; D016196:S Phase / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects
D029721:Drosophila Proteins; D009687:Nuclear Proteins; D017382:Reactive Oxygen Species; C103336:dap protein, Drosophila; D000249:Adenosine Monophosphate; D042967:Electron Transport Complex I