RRC ID 80862
Author Taouktsi E, Kyriakou E, Voulgaraki E, Verganelakis D, Krokou S, Rigas S, Voutsinas GE, Syntichaki P.
Title Mitochondrial p38 Mitogen-Activated Protein Kinase: Insights into Its Regulation of and Role in LONP1-Deficient Nematodes.
Journal Int J Mol Sci
Abstract 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 (MAPKmt), but its functional role still remains elusive. Here, we demonstrate the induction of MAPKmt 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 MAPKmt and mitochondrial Unfolded Protein Response (UPRmt) 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.
Volume 24(24)
Published 2023-12-7
DOI 10.3390/ijms242417209
PII ijms242417209
PMID 38139038
PMC PMC10743222
MeSH Animals Caenorhabditis elegans / metabolism Caenorhabditis elegans Proteins* / genetics Caenorhabditis elegans Proteins* / metabolism Cyclic AMP Response Element-Binding Protein / metabolism Mammals / metabolism Mitogen-Activated Protein Kinase 14* / metabolism Mitogen-Activated Protein Kinases / genetics Mitogen-Activated Protein Kinases / metabolism p38 Mitogen-Activated Protein Kinases / metabolism
Resource
C.elegans tm659