| Autor: |
Taouktsi E; Laboratory of Molecular Genetics of Aging, Biomedical Research Foundation of the Academy of Athens, Center of Basic Research, 11527 Athens, Greece.; Department of Biotechnology, Agricultural University of Athens, 11855 Athens, Greece., Kyriakou E; Laboratory of Molecular Genetics of Aging, Biomedical Research Foundation of the Academy of Athens, Center of Basic Research, 11527 Athens, Greece., Voulgaraki E; Laboratory of Molecular Genetics of Aging, Biomedical Research Foundation of the Academy of Athens, Center of Basic Research, 11527 Athens, Greece., Verganelakis D; Laboratory of Molecular Genetics of Aging, Biomedical Research Foundation of the Academy of Athens, Center of Basic Research, 11527 Athens, Greece.; Department of Biological Applications & Technology, University of Ioannina, 45500 Ioannina, Greece., Krokou S; Laboratory of Molecular Genetics of Aging, Biomedical Research Foundation of the Academy of Athens, Center of Basic Research, 11527 Athens, Greece., Rigas S; Department of Biotechnology, Agricultural University of Athens, 11855 Athens, Greece., Voutsinas GE; Laboratory of Molecular Carcinogenesis and Rare Disease Genetics, Institute of Biosciences and Applications, National Center for Scientific Research 'Demokritos', Aghia Paraskevi Attikis, 15341 Athens, Greece., Syntichaki P; Laboratory of Molecular Genetics of Aging, Biomedical Research Foundation of the Academy of Athens, Center of Basic Research, 11527 Athens, Greece. |
| Abstrakt: |
p38 Mitogen-Activated Protein Kinase (MAPK) cascades are central regulators of numerous physiological cellular processes, including stress response signaling. In C. elegans , mitochondrial dysfunction activates a PMK-3/p38 MAPK signaling pathway (MAPK mt ), but its functional role still remains elusive. Here, we demonstrate the induction of MAPK mt in worms deficient in the lonp-1 gene, which encodes the worm ortholog of mammalian mitochondrial LonP1. This induction is subjected to negative regulation by the ATFS-1 transcription factor through the CREB-binding protein (CBP) ortholog CBP-3, indicating an interplay between both activated MAPK mt and mitochondrial Unfolded Protein Response (UPR mt ) surveillance pathways. Our results also reveal a genetic interaction in lonp-1 mutants between PMK-3 kinase and the ZIP-2 transcription factor. ZIP-2 has an established role in innate immunity but can also modulate the lifespan by maintaining mitochondrial homeostasis during ageing. We show that in lonp-1 animals, ZIP-2 is activated in a PMK-3-dependent manner but does not confer increased survival to pathogenic bacteria. However, deletion of zip-2 or pmk-3 shortens the lifespan of lonp-1 mutants, suggesting a possible crosstalk under conditions of mitochondrial perturbation that influences the ageing process. Furthermore, loss of pmk-3 specifically diminished the extreme heat tolerance of lonp-1 worms, highlighting the crucial role of PMK-3 in the heat shock response upon mitochondrial LONP-1 inactivation. |
