Autophagy Lab

Our lab uses cellular and animal models to understand the physiological roles of autophagy and its implications during disease. Autophagy is an essential intracellular degradation pathway that recycles cell components generating new building blocks and energy to maintain cellular homeostasis. Autophagy plays an important role in the response to nutrient starvation; the recycling of damaged organelles and is a survival mechanism under stress conditions.
We are interested in the relationships between autophagy and basic processes such as proliferation, differentiation and cell death to gain insight into development and physiological aging. We want to understand how the selective removal of organelles via autophagy, such as mitophagy and pexophagy impacts the physiology of our cells and how these selective processes are regulated in vitro, in vivo and in animal models of neurodegenerative and diseases. We also seek to identify new therapies that target autophagy pathways by screening for new autophagy-modulating drugs with a view to discovering new treatments for human diseases.

Main lines of research

• Autophagy-metabolism cross talk during development and differentiation

  How the complex functionality of the nervous system arises from a pool of undifferentiated neuroepithelial cells during embryonic development is a fascinating process. We are investigating the role of autophagy in the development of the central nervous system in the mouse retina. Some autophagy deficient mice show developmental alterations that result in embryonic lethality. However, it remains unclear why autophagy is essential for proper development. We are investigating the relationship between autophagy and basic processes such as cell proliferation, differentiation, or death. Our data demonstrate that the metabolic activity of autophagy is essential to ensure proper neural differentiation in vivo and in vivo. Our research indicates that the autophagy pathways play multiple roles during embryonic development.

  We have shown that selective mitochondrial degradation, a process known as mitophagy, regulates metabolic reprogramming during neurogenesis and mitophagy deficient animals display alterations in neuronal differentiation. In addition, this role of mitophagy in regulating the metabolism seems universal since it is also observed during the polarization of macrophages to a proinflammatory phenotype. We want to understand in precise molecular regulation of mitophagy and its links to metabolism under physiological and pathological conditions.

• Autophagy and lysosomes in aging and age-related diseases

  Our laboratory is very interested in understanding how lysosomes and autophagy play a role in physiological aging. We have shown that in the aged retina there is a decrease in the cells' ability to induce autophagy and that this correlates with night vision loss and the death of light-sensitive cells, the photoreceptors. We have shown that this phenotype is very similar to that observed in the retina of autophagy-deficient animals and is also observed during retinal aging in humans.

  On the other hand, our studies show that autophagy deficient animals have a phenotype of accelerated aging being more susceptible to age-associated diseases, such as glaucoma and age macular degeneration. Our research focuses on understanding what are the alterations both at the cell and tissue level that accelerate this susceptibility. Our aim is to search for new therapeutic targets that can be used for these and other age-associated diseases

• Selective autophagy as a new therapeutic target for neurodegenerative diseases

  Defective proteostasis is one of the hallmarks of aging cells and tissues. Of the different components of the proteostasis network, we are interested in autophagy and its changes with age in retina. We have previously shown that, out of the different autophagic pathways that co-exist in all mammalian cells, macroautophagy is the first that declines with age in the retina. A crosstalk between macroautophagy and chaperone mediated autophagy (CMA) has been described whereby, in aged mice retinas, the decrease in macroautophagy correlates with increased CMA. Our working hypothesis is that aged and degenerated retinal cells increase CMA to compensate for macroautophagy loss, in an attempt to maintain cell viability. To test our hypothesis, we use histological and biochemical analysis, but also functional read outs as electroretinogram (ERG) or optic coherence tomography (OCT) and visual behavioral tests. If proven correct, increasing CMA and other selective autophagy pathways such as mitophagy could be a potential treatment to delay consequences of aging in the retina and to ameliorate degeneration in neurodegenerative and age-related retinal pathologies.

• Selected publications
  16 items2024

  Jiménez-Loygorri, J. I., Viedma-Poyatos, Álvaro, Gómez-Sintes, R., & Boya, P. (2024). Urolithin A promotes p62-dependent lysophagy to prevent acute retinal neurodegeneration. 19(1), 49. https://doi.org/10.1186/s13024-024-00739-3

  Jiménez-Loygorri, J. I., Villarejo-Zori, B., Viedma-Poyatos, Álvaro, Zapata-Muñoz, J., Benítez-Fernández, R., Frutos-Lisón, M. D., Tomás-Barberán, F. A., Espín, J. C., Area-Gómez, E., Gomez-Duran, A., & Boya, P. (2024). Mitophagy curtails cytosolic mtDNA-dependent activation of cGAS/STING inflammation during aging. 15(1), 830. https://doi.org/10.1038/s41467-024-45044-1

  2023

  Ramírez-Pardo, I., Villarejo-Zori, B., Jiménez-Loygorri, J. I., Sierra-Filardi, E., Alonso-Gil, S., Mariño, G., de la Villa, P., Fitze, P. S., Fuentes, J. M., García-Escudero, R., Ferrington, D. A., Gomez-Sintes, R., & Boya, P. (2023). Ambra1 haploinsufficiency in CD1 mice results in metabolic alterations and exacerbates age-associated retinal degeneration. 19(3), 784-804. https://doi.org/10.1080/15548627.2022.2103307

  2022

  Wilhelm, L. P., Zapata-Muñoz, J., Villarejo-Zori, B., Pellegrin, S., Freire, C. M., Toye, A. M., Boya, P., & Ganley, I. G. (2022). BNIP3L/NIX regulates both mitophagy and pexophagy. 41(24), e111115. https://doi.org/10.15252/embj.2022111115

  Gomez-Sintes, R., Xin, Q., Jimenez-Loygorri, J. I., , Diaz, A., Garner, T. P., Cotto-Rios, X. M., Wu, Y., Dong, S., Reynolds, C. A., Patel, B., de la Villa, P., Macian, F., Boya, P., Gavathiotis, E., & Cuervo, A. M. (2022). Targeting retinoic acid receptor alpha-corepressor interaction activates chaperone-mediated autophagy and protects against retinal degeneration. 13(1), 4220. https://doi.org/10.1038/s41467-022-31869-1

  Orhon, I., Rocchi, C., Villarejo-Zori, B., Serrano Martinez, P., Baanstra, M., Brouwer, U., Boya, P., Coppes, R., & Reggiori, F. (2022). Autophagy induction during stem cell activation plays a key role in salivary gland self-renewal. 18(2), 293-308. https://doi.org/10.1080/15548627.2021.1924036

  2021

  Samardzija, M., Corna, A., Gomez-Sintes, R., Jarboui, M. A., Armento, A., Roger, J. E., Petridou, E., Haq, W., Paquet-Durand, F., Zrenner, E., de la Villa, P., Zeck, G., Grimm, C., Boya, P., Ueffing, M., & Trifunović, D. (2021). HDAC inhibition ameliorates cone survival in retinitis pigmentosa mice. 28(4), 1317-1332. https://doi.org/10.1038/s41418-020-00653-3

  2019

  Bravo-San Pedro, J. M., Sica, V., Martins, I., Pol, J., Loos, F., Maiuri, M. C., Durand, S., Bossut, N., Aprahamian, F., Anagnostopoulos, G., Niso-Santano, M., Aranda, F., Ramírez-Pardo, I., Lallement, J., Denom, J., Boedec, E., Gorwood, P., Ramoz, N., Clément, K., Pelloux, V., Rohia, A., Pattou, F., Raverdy, V., Caiazzo, R., Denis, R. G. P., Boya, P., Galluzzi, L., Madeo, F., Migrenne-Li, S., Cruciani-Guglielmacci, C., Tavernarakis, N., López-Otín, C., Magnan, C., & Kroemer, G. (2019). Acyl-CoA-Binding Protein Is a Lipogenic Factor that Triggers Food Intake and Obesity. 30(4), 754-767.e9. https://doi.org/10.1016/j.cmet.2019.07.010

  , Prescott, A. R., Villarejo-Zori, B., Ball, G., Boya, P., & Ganley, I. G. (2019). A comparative map of macroautophagy and mitophagy in the vertebrate eye. 15(7), 1296-1308. https://doi.org/10.1080/15548627.2019.1580509

  2017

  Esteban-Martínez, L., Sierra-Filardi, E., , Salazar-Roa, M., Mariño, G., Seco, E., Durand, S., Enot, D., Graña, O., Malumbres, M., Cvekl, A., Cuervo, A. M., Kroemer, G., & Boya, P. (2017). Programmed mitophagy is essential for the glycolytic switch during cell differentiation. 36(12), 1688-1706. https://doi.org/10.15252/embj.201695916

  2015

  Doménech, E., Maestre, C., Esteban-Martínez, L., Partida, D., Pascual, R., Fernández-Miranda, G., Seco, E., Campos-Olivas, R., Pérez, M., Megias, D., Allen, K., López, M., Saha, A. K., Velasco, G., Rial, E., Méndez, R., Boya, P., Salazar-Roa, M., & Malumbres, M. (2015). AMPK and PFKFB3 mediate glycolysis and survival in response to mitophagy during mitotic arrest. 17(10), 1304-1316. https://doi.org/10.1038/ncb3231

  2013

  Rodríguez-Muela, N., Koga, H., García-Ledo, L., de la Villa, P., de la Rosa, E. J., Cuervo, A. M., & Boya, P. (2013). Balance between autophagic pathways preserves retinal homeostasis. 12(3), 478-488. https://doi.org/10.1111/acel.12072

  2012

  Vázquez, P., Arroba, A. I., Cecconi, F., de la Rosa, E. J., Boya, P., & de Pablo, F. (2012). Atg5 and Ambra1 differentially modulate neurogenesis in neural stem cells. 8(2), 187-199. https://doi.org/10.4161/auto.8.2.18535

  Rodríguez-Muela, N., Germain, F., Mariño, G., Fitze, P. S., & Boya, P. (2012). Autophagy promotes survival of retinal ganglion cells after optic nerve axotomy in mice. 19(1), 162-169. https://doi.org/10.1038/cdd.2011.88

  2010

  Dehay, B., Bové, J., Rodríguez-Muela, N., Perier, C., Recasens, A., Boya, P., & Vila, M. (2010). Pathogenic lysosomal depletion in Parkinson’s disease. 30(37), 12535-12544. https://doi.org/10.1523/JNEUROSCI.1920-10.2010

  2008

  Mellén, M. A., de la Rosa, E. J., & Boya, P. (2008). The autophagic machinery is necessary for removal of cell corpses from the developing retinal neuroepithelium. 15(8), 1279-1290. https://doi.org/10.1038/cdd.2008.40