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Nitrogen stress activates AMPK

AMPK inhibits TORC1 signaling in response to nitrogen stress. The removal of all nitrogen sources from the growth medium (nitrogen starvation) causes the fission yeast Schizosaccharomyces pombe to undergo mitotic arrest. However, transferring S. pombe from medium containing a good nitrogen source (glutamate) to medium containing a poor nitrogen source (proline) causes nitrogen stress, during which the cells continue to proliferate but are smaller than cells grown on glutamate. Davie et al. found that nitrogen stress reduced the size threshold for mitotic commitment in S. pombe. Using proline consumes more energy than does using glutamate, and transferring cells from glutamate- to proline-containing growth medium indeed induced a transient reduction in adenosine triphosphate (ATP) abundance, but the cells recovered within a few minutes. A reduction in the amount of ATP relative to that of AMP activates adenosine monophosphate (AMP)–activated protein kinase (AMPK), which in turn inhibits signaling through the target of rapamycin complex 1 (TORC1) to reduce protein synthesis and cell growth. The catalytic AMPK α subunit Ssp2 (AMPKαSsp2) was required to reduce the mitotic size threshold in response to nitrogen stress, and cells lacking AMPKαSsp2 had increased TORC1 signaling. The regulatory β and γ subunits, which mediate activation of AMPK in response to reduced ATP, were not required for the response to nitrogen stress, implying that the transient drop in ATP abundance after the induction of nitrogen stress was not responsible for AMPK activation in this context. Additional experiments indicated that AMPKαSsp2 was not required for TORC1 inhibition induced by amino acid deprivation. In cells grown on glutamate-containing medium, the calcium/calmodulin–dependent protein kinase kinase (CaMKK) homolog Ssp1 (CaMKKSsp1) and protein phosphatase 2C (PP2C) maintained the steady-state phosphorylation status of AMPKαSsp2. Nitrogen starvation increases CaMKKSsp1-mediated phosphorylation of AMPKαSsp2 and nuclear translocation of AMPK, resulting in mitotic arrest. However, the reduction in the mitotic size threshold caused by nitrogen stress required CaMKKPpk34-mediated phosphorylation of AMPKαSsp2. It is possible that changing nitrogen conditions also modulate signaling through mammalian TORC1 (mTORC1), because replacing glutamine in the culture medium with ammonia, a normal metabolic byproduct, transiently inhibited mTORC1 in human Hep3B heptoma cells. Thus, AMPK can modulate TORC1 signaling in response to changes in nitrogen availability in addition to changes in cellular energy status. E. Davie, G. M. A. Forte, J. Petersen, Nitrogen regulates AMPK to control TORC1 signaling. Curr. Biol. 25, 445–454 (2015). [PubMed]