Where Ideas grow

Yeast Signalling Networks

ABOUT

Our research focuses on the interplay between cell signalling pathways in the regulation of mitochondria and vacuoles, two organelles with key roles in cellular homeostasis and lifespan. We use genetic, biochemical and lipidomic approaches to identify effectors of signalling proteins whose modulation counteracts the decline of cell functions during ageing and in a model of lysosomal disease.

 

RESEARCH

We showed that Sit4 (PP6 orthologue) and Sch9 (S6K orthologue), two effectors of the nutrient signalling kinase TORC1, act as ceramide sensors whose improper activation leads to premature aging in yeast lacking the neutral sphingomyelinase Isc1. Deregulation of TORC1-Sch9 and Sit4 impairs vesicular trafficking, vacuolar functions and autophagy, and promotes Dnm1-dependent mitochondrial fragmentation, decreasing lifespan. Moreover, we uncovered that hexokinase 2 functions downstream of Sit4 in the control of cell cycle, mitochondria and lifespan.
We also identified Hog1 (p38 orthologue) as a protein kinase that directly regulates the low-iron sensing transcription factor Aft1, and showed that Aft1-Hog1 interaction decreases in Isc1 deficient cells, linking sphingolipid signalling to iron homeostasis.
Our studies also demonstrated that the accumulation of sphingosines and ceramides is conserved in a yeast model of Niemann-Pick type C (NPC1) disease. We showed for the first time that activation of Pkh1-Sch9 and Sit4 by sphingolipids mediates the mitochondrial dysfunction and shortened lifespan exhibited by this model.
We also implicated the ADP/ATP carrier and ceramide in mitochondrial outer membrane permeabilization and cytochrome c release during yeast apoptosis. A yeast model of Parkinson´s disease associated with LRRK2 mutations was also implemented.
Collaborators: Yusuf Hannun (Stony Brook Univ., NY, USA), Francesc Posas (Universitat Pompeu Fabra, Barcelona, Spain), Andjelka ?eli? (University of Novi Sad, Serbia), and Manuela Côrte-Real (Univ. of Minho).

Fluorescence microscopy image of the yeast mitochondrial network (green) and vacuoles (red).

Selected Publications

Vilaça R., Barros I., Matmati N., Silva E., Martins T., Teixeira V., Hannun Y., Costa V.,
The ceramide activated protein phosphatase Sit4 impairs sphingolipid dynamics, mitochondrial function and lifespan in a yeast model of Niemann-Pick type C1. Biochimica et Biophysica Acta - Molecular Basis of Disease1864(1):79-88, 2018. [Journal: Article] [CI: 2] [IF: 4,3]
DOI: 10.1016/j.bbadis.2017.10.010 SCOPUS: 85031804747. .

Martins T., Pereira C., Canadell D., Vilaça R., Teixeira V., Moradas-Ferreira P., de Nadal E., Posas F., Costa V.,
The Hog1p kinase regulates Aft1p transcription factor to control iron accumulation. Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids1863(1):61-70, 2018. [Journal: Article] [CI: 3] [IF: 4,4]
DOI: 10.1016/j.bbalip.2017.10.001 SCOPUS: 85032229876. .

Teixeira V., Medeiros T., Vilaça R., Ferreira J., Moradas-Ferreira P., Costa V.,
Ceramide signaling targets the PP2A-like protein phosphatase Sit4p to impair vacuolar function, vesicular trafficking and autophagy in Isc1p deficient cells. Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids1861(1):21-33, 2016. [Journal: Article] [CI: 6] [IF: 5,5]
DOI: 10.1016/j.bbalip.2015.10.004 SCOPUS: 84944937082. .

Teixeira V., Costa V.,
Unraveling the role of the Target of Rapamycin signaling in sphingolipid metabolism. Progress in Lipid Research61:109-133, 2016. [Journal: Review] [CI: 13] [IF: 10,6]
DOI: 10.1016/j.plipres.2015.11.001 SCOPUS: 84952328556. .

Pereira C., Costa V., Martins L., Saraiva L.,
A yeast model of the Parkinson's disease-associated protein Parkin. Experimental Cell Research333(1):73-79, 2015. [Journal: Article] [CI: 17] [IF: 3,4]
DOI: 10.1016/j.yexcr.2015.02.018 SCOPUS: 84926408656. .

Vilaça R., Silva E., Nadais A., Teixeira V., Matmati N., Gaifem J., Hannun Y., Sá Miranda M., Costa V.,
Sphingolipid signalling mediates mitochondrial dysfunctions and reduced chronological lifespan in the yeast model of Niemann-Pick type C1. Molecular Microbiology91(3):438-451, 2014. [Journal: Article] [CI: 16] [IF: 4,4]
DOI: 10.1111/mmi.12470 SCOPUS: 84908101723. .

Barbosa A., Osório H., Sims K., Almeida T., Alves M., Bielawski J., Amorim M., Moradas-Ferreira P., Hannun Y., Costa V.,
Role for Sit4p-dependent mitochondrial dysfunction in mediating the shortened chronological lifespan and oxidative stress sensitivity of Isc1p-deficient cells. Molecular Microbiology81(2):515-527, 2011. [Journal: Article] [CI: 32] [IF: 5]
DOI: 10.1111/j.1365-2958.2011.07714.x SCOPUS: 79960193275. .

Mesquita A., Weinberger M., Silva A., Sampaio-Marques B., Almeida B., Leão C., Costa V., Rodrigues F., Burhans W., Ludovico P.,
Caloric restriction or catalase inactivation extends yeast chronological lifespan by inducing H 2 O 2 and superoxide dismutase activity. Proceedings of the National Academy of Sciences of the United States of America107(34):15123-15128, 2010. [Journal: Article] [CI: 155] [IF: 9,8]
DOI: 10.1073/pnas.1004432107 SCOPUS: 77956987110. .

Almeida T., Marques M., Mojzita D., Amorim M., Silva R., Almeida B., Rodrigues P., Ludovico P., Hohmann S., Moradas-Ferreira P., Côrte-Real M., Costa V.,
Isc1p plays a key role in hydrogen peroxide resistance and chronological lifespan through modulation of iron levels and apoptosis. Molecular Biology of the Cell19(3):865-876, 2008. [Journal: Article] [CI: 61] [IF: 5,6]
DOI: 10.1091/mbc.E07-06-0604 SCOPUS: 41649101223. .

Costa V., Amorim M., Quintanilha A., Moradas-Ferreira P.,
Hydrogen peroxide-induced carbonylation of key metabolic enzymes in Saccharomyces cerevisiae: The involvement of the oxidative stress response regulators Yap1 and Skn7. Free Radical Biology and Medicine33(11):1507-1515, 2002. [Journal: Article] [CI: 116] [IF: 5,5]
DOI: 10.1016/S0891-5849(02)01086-9 SCOPUS: 0036890134. .