A contribution of budding yeast to unravel aging. Entry into quiescence relies on the transceptor Mtl1 by sensing nutrients and regulation of signaling pathways
Universitat de Lleida. Departament de Ciències Mèdiques Bàsiques
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Saccharomyces cerevisiae is a premier model system to study ageing in post mitotic cells. In this study, we show that Mtl1, member of the Cell Wall Integrity pathway (CWI), plays a positive role in Chronological Life Span (CLS). The absence of Mtl1 shortens CLS whereas its overexpression extends
it. In mtl1 cells, we observe mitochondrial dysfunction during diauxic shift that is reflected in i) increase in uncoupled respiration associated to low oxygen consumption; ii) significant increase in mitochondrial membrane potential; iii) ROS (Reactive Oxygen Species) accumulation and as well as iv) a descent in aconitase activity. We demonstrate that this mitochondrial dysfunction observed in mtl1 mutant is a consequence of improper regulation of key signaling pathwaysrequired for entry in quiescence. TOR1/SCH9 deletion and less effectively PKA (Protein Kinase A) inactivation in mtl1 not only suppressed the mitochondrial defects but also increased the CLS. Mtl1 links mitochondrial dysfunction with TOR (Target of Rapamycin) and PKA pathways in quiescence. In the absence of Mtl1, the stability of the inhibitory subunit of PKA, Bcy1 is severely reduced, mainly as a consequence of a high PKA activity. Mtl1 regulates PKA inactivation through Bcy1 phosphorylation, both in diauxic conditions and mainly in response to glucose depletion. In these conditions, Mtl1 negatively regulates Tor1/Sch9 function to phosphorylate Bcy1 and thus to inhibit PKA through phosphorylation of Bcy1 by Slt2 MAPK, although additional kinases might be also involved in this signal. We also show that Mtl1 function in CLS does not totally depend on CWI pathway since mtl1slt2 double mutant presents synthetic lethality. Mtl1 acts as a glucose sensor thereby it regulates both NCR (Nitrogen Catabolite Repression) and RTG (Retrograde Response Mitochondrial- Nucleus) pathways through Snf1 kinase upon glucose depletion, although independent of TORC1 and PKA functions. Again, additional targets are not completely ruled out. In conclusion, Mtl1 is an efficient transceptor involved in sensing and signaling nutrient availability in quiescence, mainly glucose, and in regulating multiple pathways involved in life extension.
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