Editors' ChoiceCell Metabolism

Placing the nuclear pore in the metformin mechanism of action

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Sci. Signal.  03 Jan 2017:
Vol. 10, Issue 460, eaam6836
DOI: 10.1126/scisignal.aam6836

Metformin reduces cellular ATP and restricts passive transport through the nuclear pore to limit nuclear activation of a protein that activates mTORC1.

Metformin is a drug that alters cellular metabolism and that is used to treat type 2 diabetes and may also be beneficial in treating cancer. To investigate the mechanism of action for metformin, Wu et al. used the model organism Caenorhabditis elegans and identified the C. elegans ortholog of acyl-CoA dehydrogenase 10 (CeACAD10) as a gene induced at the transcriptional and translational levels by metformin or another biguanide, phenformin. Using this transcriptional response as a readout of biguanide action, the authors identified a pathway that connected mitochondrial dysfunction (reduced ATP concentration) to inhibition of the passive transport function of the nuclear pore complex (NPC) and the inability to activate a key stimulator of mechanistic target of rapamycin complex 1 (mTORC1). The guanosine trisphosphatase (GTPase) complex of RagA and RagC activates mTORC1 when RagA is GTP-bound and RagC is guanosine diphosphate (GDP)–bound. RagC has a nuclear export sequence but no nuclear import sequence, suggesting that RagC may move passively into the nucleus. Under basal conditions in human cultured cells, RagC had a nuclear and cytoplasmic distribution; phenformin triggered the loss of RagC from the nucleus. In cells expressing various mutants of the RagA/RagC complex in which the proteins were locked in active or inactive conformations, analysis of the nuclear and cytoplasmic distribution of RagC indicated that RagA in the GDP-bound state was necessary for RagC in the GTP-bound state to move into the nucleus. Furthermore, nuclear translocation was necessary to convert RagC to the active GDP-bound state. The GTPase-activating protein (GAP) activity for RagC was most abundant in the nucleus and the GAP folliculin was detected in the nucleus. Thus, this study identifies an activation event for a positive regulator of mTORC1 that occurs specifically in the nucleus and indicates that the NPC function is regulated by cellular ATP balance. Castillo-Quan and Blackwell discuss the implications of this study for the lifespan-promoting effects and the anticancer effects of metformin.

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