A contribution of budding yeast to unravel aging. Entry into quiescence relies on the transceptor Mtl1 by sensing nutrients and regulation of signaling pathways
Issue date
2015-01-10Author
Sundaram, Venkatraghavan
Other authors
Universitat de Lleida. Departament de Ciències Mèdiques Bàsiques
Suggested citation
Sundaram, Venkatraghavan.
(2015)
.
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.
L.227-2015
;
http://hdl.handle.net/10803/286033.
Metadata
Show full item recordSaccharomyces 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.
European research projects
Collections
- Tesis Doctorals [1310]