The research, which appears detailed in the magazine Nature Communicationsdescribes “unexpected connections” between molecular machinery that regulates apoptosis or programmed cell death and autophagy, a process by which cells digest or recycled some of its parts to heal And, at the same time, achieve energy.
Apoptosis is a genetically programmed form of cell death that, under normal conditions, is completely invisible to the immune system. However, in certain cases, this process can induce an immune response against the same cells that are being destroyed.
In recent years, the concept of immunogenic cell death (ICD) has emerged, a type of apoptosis that stimulates that morboundary cancer cells promote an immune response. There are currently certain chemotherapy and radiotherapy treatments that can induce this type of cell death in tumor cells.
“Immunogenic cell death is capable of producing antitumoral immune responses that contribute to tumor remission and, therefore, presents relevance in cancer,” explains the main author of this work, the CBM-CSIC-UAM researcher Felipe X. Pimentel-Muiños. “Although the mechanisms that regulate the immunogenic potential of apoptosis are not known clearly, we do know that they imply the secretion of agents that stimulate the immune response, such as the ATP energy molecule,” clarifies the CBM researcher.
Autophagy
In addition to apoptosis, there is an alternative process that, if it manifests in an exacerbated way, can lead to cell death. This is autophagy, a mechanism that has captured the attention of scientists in recent years for their involvement in complex processes that control cell life and in the development of various pathologies. during the autophagy -it claims in the survival of the cells, since it serves to recycle damaged parts or molecules -, the processing of the substrates that are recycled generates the ATP molecule, which constitutes an alternative energy source for cells in stress situations. In this sense, under hostile conditions such as hypoxia or lack of nutrients, the process can be shot in an exaggerated way leading to cell death.
“Autophagy is an evolutionarily preserved phenomenon that plays an important role in the prevention of various pathologies, such as cancer, inflammatory diseases and neurodegenerative Pimentel-Muiños.
-An atypical autophagy mechanism
In this work, researchers detail that there is an atypical autophagy mechanism that is capable of connecting cell machinery involved in apopotosis with the suppression of an immune response associated with cell death. This route is mediated by the formation in the cells of small compartments delimited by a membrane, called unconventional cytoplasmic vesicles, which kidnap the ATP molecule and prevent their release throughout the apoptosis process.
“A detailed examination of these vesicles indicates that they have autophagy markers. In addition, the process that we have seen gives rise to the formation of a new protein complex in the mitochondria of the cells, which activates a part of a molecule involved in autophagy (called ATG16L1), whose function is not necessary for the conventional autophagic route,” says the CBM researcher.
Through this new mechanism, the ATG16L1 molecule represses immunogenicity associated with the cell death of apoptosis, preventing ATP secretion. “This work opens the door to the design of strategies aimed at inhibiting the unconventional ATG16L activity and thus improving the potential of cell death induced by chemotherapy. In addition, given that the route involved presents unconventional mechanisms, it would be possible to perform that inhibition without altering the autophagy processes that help maintain the balance of the cells,” he concludes Pimplyl.
Scientific reference:
Elena Terraza-Silvestre; Raquel Villamuera; Julia Bandera-Linero; Michal Letek; Daniel Oña Sánchez; Cristina Ramón-Barros; Clara Moyano-Jimeno; Felipe X. Pimentel-Muiños. An unconventional autophagic pathway that inhibits atp secretion during apoptotic cell death. Nature Communications. DOI: 10.1038/S41467-025-58619-3
Fuente: CSIC
