I started my scientific career at the University of Basque Country (UPV-EHU), where I did a Bachelor degree in Biochemistry and Molecular Biology obtaining first-class honours degree, and a Master in Biomedicine and Molecular Biology. During this period, I was student under Dr. Gorka Basañez’ supervision at the Biofisika Institutua (UPV/EHU). Here, I studied the role of mitochondrial lipids in the BCL-2 family proteins interaction network, key regulators of mitochondrial apoptosis, and gained knowledge in different biophysical and biochemical techniques including model membrane systems and protein purification methodologies.

During my PhD studies, also based at the Basañez lab, I focused on the characterization of the membrane topology of the apoptotic effector BAX (PMID: 29176554) and on understanding the role of BFL1 in the apoptotic network (PMID: 30560933), acquiring strong skills in structural biology, cell biology and microscopy. In the former publication, we characterized the membrane conformation of BAX. Understanding the structure of the BCL2 proteins (to which BAX belongs to) has contributed to the rational design of drugs to kill cancer cells. This is the case for Venetoclax, currently used to treat some lymphomas (including AML, CLL and SML). BAX undergoes a profound rearrangement in the membrane during its activation process that has challenged the generation of compounds for its regulation. Thus, our work is important for the rational design of molecules that act at the membrane level (where BAX elicits its function) to regulate its activity in order to tune cell death. Additionally, it could be beneficial in degenerative processes in which excessive cell death is causing pathological situations (e.g. Alzheimer’s, Parkinson’s etc). In the second work, we characterized the role of BFL1, a less studied member of the BCL-2 family, by using a multidisciplinary approach and cutting-edge microscopy techniques (e.g. SFCCS, TIRF). We gained important information about the binding affinity of BFL1 for different family members, the relevant interaction surfaces, and the role of the mitochondrial lipid cardiolipin altering the affinities between the different family member, as well as uncovering a prodeath mode of this protein through which it promotes, rather than inhibits, cell death. This prodeath activity offers an additional targetable therapeutic scenario to regulate apoptotic cell death.

Next, I moved to Germany to Ana J. Garcia-Saez lab (first in the IFIB at the University of Tübingen and currently at the CECAD, in the University of Cologne) as a postdoctoral scientist. Here, I expanded the characterization of the BCL-2 proteins to other cellular functions beyond apoptosis. One example is PMID: 34931711, where we found that tBID, a protein belonging to the BCL-2 family, can replace the canonical effectors BAX and BAK in the execution of apoptosis and that this membrane permeabilization activity can be relevant to kill leukemia cells and during Shigella flexneri bacterial infection. We believe that this observation is extremely interesting to the field as it uncovers a new effector protein of apoptosis to combat cancer and infection. Another key aspect of my postdoc has been the characterization of the Mitochondria-ER contact sites (MERCS). These structures constitute signalling platforms for a wide variety of cellular processes (e.g. calcium signalling or autophagy) and their dysregulation is frequently associated with human diseases (e.g. Parkinson’s and Alzheimer’s). In the Garcia-Saez lab, I had the opportunity to learn different advanced microscopy techniques ideal to tackle these organelles and to develop a biosensor suitable for their analysis (PMID: 31818884). This biosensor is a fast and reliable tool to tackle MERCS that I believe had a positive impact in the community due to its versatility.

Currently, I am Ikerbasque research fellow at Achucarro centre, where I started my own lab to decipher the role of intracellular contact sites in Neuropathology.

Twitter account (@floresromeroh)