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Mitochondria Biology & Neurodegeneration

Mitochondria at the synapse have a pivotal role in neurotransmitter release, but almost nothing is known about synaptic mitochondria composition or specific functions. Synaptic mitochondria compared to mitochondria in other cells, need to cope with increased calcium load, more oxidative stress, and high demands of energy generation during synaptic activity. We aim to unravel how synaptic mitochondria have learnt to adapt to this environment, and how the disruption of these acquired mechanisms contributes to neurodegeneration.

More intriguing is the question how mitochondria sense their unhealthy status and decide whether their failure should lead to removal of the organelle or dismissal of the complete neuron via cell death. We anticipate that these decisions are not only operational during disease, but might constitute a fundamental mechanism relevant for maintenance of synaptic activity and establishment of new synapses. We plan to identify key players of the proposed regulatory pathways involved in intrinsic mitochondria quality control.

Mitochondrial dysfunction has been implicated in several neurodegenerative disorders, namely Parkinson's Disease. Our work will unravel the specific properties of synaptic mitochondria and provide much needed insight in their hypothesized predominant role in neurodegeneration.

Research Team

Ana Beatriz Ramos
MSc Student
bramos@medicina.ulisboa.pt

Andreia Faria-Pereira
PhD Student
andreiapereira@medicina.ulisboa.pt

Bernardo Cetra Antunes
Lab Technician
bernardo.antunes@medicina.ulisboa.pt

Carlos C. Ramos
PhD Student
carlos.ramos@medicina.ulisboa.pt

Elvira P. Leites
PhD Student
elviraleites@medicina.ulisboa.pt

Filipa B. Gonçalves
PhD Student
filipagoncalves@medicina.ulisboa.pt

Filipa L. Carvalho
Post-Doctoral Researcher
filipa.carvalho@medicina.ulisboa.pt

Filipe Cortes-Figueiredo
PhD Student

Rita A. Soares
PhD Student
ritasoares@medicina.ulisboa.pt

Research Areas

  • Regulation of Mitochondria Quality Control pathways in neurons
  • Mechanisms of regulation of Synaptic Mitochondria
  • Mitochondria dysfunction in Neurodegenerative Disorders

Ongoing Research Projects

2016-2021 European Research Council ERC-Starting Grant - SynapticMitochondria  

2016-2018 EMBO Installation Grant - Homeostasis and Maintenance of Synaptic Mitochondria

2015-2020 Investigador FCT 2015 Award

Awards

2015-2020 Investigator FCT Award

March 2015  ADPD Junior Faculty Award. Awarded bi-annually to selected promising scientists.

2008-2010 Postdoctoral Research fellowship (BPD) FCT, Portugal.

2006 EMBO Short Term fellowship

2006-2008  Marie-Curie foundation Postdoctoral fellowship.

2001-2006 PhD fellowship (BD) from FCT, Portugal.

Selected Publications

Publications arising from Post Doctoral work:

O'Flanagan, C.H., Morais, V.A., O'Neill, C. (2016) PINK1, cancer and neurodegeneration. Oncoscience. 3(1):1-2.

Aerts, L., Craessaerts, K., De Strooper, B., Morais, V.A. (2016) In Vitro Comparison of the Activity Requirements and Substrate Specificity of Human and Triboleum castaneum PINK1 Orthologues. PLoS One. 11(1):e0146083.

Aerts, L., Craessaerts, K., De Strooper, B.*, Morais, V.A.* (2015). PINK1 Kinase Catalytic Activity Is Regulated by Phosphorylation on Serines 228 and 402. J Biol Chem. 290: 2798-811. Citation: 10 *shared corresponding authors

Aerts, L., De Strooper, B., Morais, V.A.* (2015). PINK1 activation-turning on a promiscuous kinase. Biochem Soc Trans. 43(2):280-6. Citation: 4

O’ Flanagan, C., Morais, V.A., Wurst, W., De Strooper, B., O’ Neill, C. (2014). The Parkinson’s gene PINK1 regulates cell cycle progression and promotes cancer-associated phenotypes, Oncogene, 00:00. Citation: 10

Morais, V.A.*, Haddad, D., Craessaerts, K., De Bock, P., Swerts, J., Vilain, S., Aerts, L., Overbergh, L., Grünewald, A., Seibler, P., Klein, C., Gevaert, K., Verstreken, P., De Strooper, B.* (2014). PINK1 Loss of Function Mutations Affect Mitochondrial Complex I Activity via NdufA10 Ubiquinone Uncoupling, Science, 344 (6180), 203-207. Citation: 66 *shared corresponding authors

Vos, M., Lovisa, B., Geens, A., Morais, V.A., Wagnières, G., van den Bergh, H., Ginggen, A., De Strooper, B., Tardy, Y., Verstreken, P. (2013). Near-Infrared 808 nm Light Boosts Complex IV-Dependent Respiration and Rescues a Parkinson-Related pink1 Model, PLoS One, 8 (11), e78562. Citation: 10

Haddad, D., Vilain, S., Vos, M., Esposito, G., Matta, S., Kalscheuer, V., Craessaerts, K., Leyssen, M., Nascimento, R., Vianna-Morgante, A., De Strooper, B., Van Esch, H., Morais, V.A.*, Verstreken, P.* (2013). Mutations in the Intellectual Disability Gene Ube2a Cause Neuronal Dysfunction and Impair Parkin-Dependent Mitophagy, Molecular cell, 50 (6), 831-43. Citation: 32 *shared corresponding authors

Mandemakers, W., Abuhatzira, L., Xu, H., Caromile, L., Hébert, S., Snellinx, A., Morais, V.A., Matta, S., Cai, T., Notkins, A., De Strooper, B. (2013). Co-regulation of intragenic microRNA miR-153 and its host gene Ia-2 β: identification of miR-153 target genes with functions related to IA-2β in pancreas and brain, Diabetologia, 56 (7), 1547-56. Citation: 14

Vos, M., Esposito, G., Edirisinghe, J., Vilain, S., Haddad, D., Slabbaert, J., Van Meensel, S., Schaap, O., De Strooper, B., Meganathan, R., Morais, V.A., Verstreken, P. (2012). Vitamin K2 is a mitochondrial electron carrier that rescues pink1 deficiency, Science, 336 (6086), 1306-10. Citation: 129

Vilain, S., Esposito, G., Haddad, D., Schaap, O., Dobreva, M., Vos, M., Van Meensel, S., Morais, V.A., De Strooper, B., Verstreken, P. (2012). The yeast complex I equivalent NADH dehydrogenase rescues pink1 mutants, PLoS Genetics, 8 (1), e1002456. Citation: 52

Matta, S., Van Kolen, K., da Cunha, R., van den Bogaart, G., Mandemakers, W., Miskiewicz, K., De Bock, P., Morais, V.A., Vilain, S., Haddad, D., Delbroek, L., Swerts, J., Chávez-Gutiérrez, L., Esposito, G., Daneels, G., Karran, E., Holt, M., Gevaert, K., Moechars, D., De Strooper, B., Verstreken, P. (2012). LRRK2 Controls an EndoA Phosphorylation Cycle in Synaptic Endocytosis, Neuron, 75 (6), 1008-1021. Citation: 121

Morais, V.A., De Strooper, B. (2010). Mitochondria Dysfunction and Neurodegenerative Disorders: Cause or Consequence, Journal of Alzheimer's Disease, 20 Suppl 2, S255-63. Citation: 74

Morais, V.A., Verstreken, P., Roethig, A., Smet, J., Snellinx, A., Vanbrabant, M., Haddad, D., Frezza, C., Mandemakers, W., Vogt-Weisenhorn, D., Van Coster, R., Wurst, W., Scorrano, L., De Strooper, B. (2009). Parkinson's disease mutations in PINK1 result in decreased Complex I activity and deficient synaptic function, EMBO Molecular Medicine, 1 (2), 99-111. Citation: 187

Mandemakers, W., Morais, V.A., De Strooper, B. (2007). A cell biological perspective on mitochondrial dysfunction in Parkinson disease and other neurodegenerative diseases, Journal of Cell Science, 120, 1707-1716. Citation: 145

Publications arising from PhD work:

Escrevente, C., Morais, V.A., Keller, S., Soares, C., Altevogt, P., Costa, J. (2008). Functional role of N-glycosylation from ADAM10 in processing, localization and activity of the enzyme, Biochimica et Biophysica Acta. General Subjects, 1780 (6), 905-913. Citation: 48

Morais, V.A., Leight, S., Pijak, D., Lee, V., Costa, J. (2008). Cellular localization of Nicastrin affects amyloid beta species production, FEBS Letters, 582 (3), 427-433. Citation: 8

Gouveia, R., Morais, V.A., Peixoto, C., Sousa, M., Regalla, M., Alves, P., Costa, J. (2007). Production and purification of functional truncated soluble forms of human recombinant L1 cell adhesion glycoprotein from Spodoptera frugiperda Sf9 cells, Protein Expression and Purification, 52 (1), 182-193. Citation: 18

Morais, V.A., Brito, C., Pijak, D., Crystal, A., Fortna, R., Li, T., Wong, P., Doms, R., Costa, J. (2006). N-glycosylation of human nicastrin is required for interaction with the lectins from the secretory pathway calnexin and ERGIC-53, Biochimica et Biophysica Acta. Molecular Basis of Disease, 1762 (9), 802-810. Citation: 26

Marcos, N., Pinho, S., Grandela, C., Cruz, A., Samyn-Petit, B., Harduin-Lepers, A., Almeida, R., Silva, F., Morais, V.A., Costa, J., Kihlberg, J., Clausen, H., Reis, C. (2004). Role of the human ST6GalNAc-I and ST6GalNAc-II in the synthesis of the cancer-associated sialyl-Tn antigen, Cancer Research, 64 (19), 7050-7057. Citation: 114

Crystal, A., Morais, V.A., Fortna, R., Carlin, D., Pierson, T., Wilson, C., Lee, V., Doms, R. (2004). Presenilin modulates Pen-2 levels posttranslationally by protecting it from proteasomal degradation, Biochemistry, 43 (12), 3555-3563. Citation: 45

Fortna, R., Crystal, A., Morais, V.A., Pijak, D., Lee, V., Doms, R. (2004). Membrane topology and nicastrin-enhanced endoproteolysis of APH-1, a component of the gamma-secretase complex, Journal of Biological Chemistry, 279 (5), 3685-3693. Citation: 78

Palma, A., Morais, V.A., Coelho, A., Costa, J. (2004). Effect of the manganese ion on human alpha 3/4 fucosyltransferase III activity, Biometals, 17 (1), 35-43. Citation: 14

Morais, V.A., Crystal, A., Pijak, D., Carlin, D., Costa, J., Lee, V., Doms, R. (2003). The transmembrane domain region of nicastrin mediates direct interactions with APH-1 and the gamma-secretase complex, Journal of Biological Chemistry, 278 (44), 43284-43291. Citation: 85

Morais, V.A., Costa, J. (2003). Stable expression of recombinant human alpha 3/4 fucosyltransferase III in Spodoptera frugiperda Sf9 cells, Journal of Biotechnology, 106 (1), 69-75. Citation: 20

Morais, V.A., Costa, M., Costa, J. (2003). N-glycosylation of recombinant human fucosyltransferase III is required for its in vivo folding in mammalian and insect cells, Biochimica et Biophysica Acta. General Subjects, 1619 (2), 133-138. Citation: 26

Crystal, A., Morais, V.A., Pierson, T., Pijak, D., Carlin, D., Lee, V., Doms, R. (2003). Membrane topology of gamma-secretase component PEN-2, Journal of Biological Chemistry, 278 (22), 20117-20123. Citation: 104

Morais, V.A., Serpa, J., Palma, A., Costa, T., Maranga, L., Costa, J. (2001). Expression and characterization of recombinant human alpha-3/4-fucosyltransferase III from Spodoptera frugiperda (Sf9) and Trichoplusia ni (Tn) cells using the baculovirus expression system, Biochemical Journal, 353, 719-725. Citation: 35  

group leader :
Vanessa A. Morais