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Mitochondrial p38 Mitogen-Activated Protein Kinase: Insights into Its Regulation of and Role in LONP1-Deficient Nematodes
oleh: Eirini Taouktsi, Eleni Kyriakou, Evangelia Voulgaraki, Dimitris Verganelakis, Stefania Krokou, Stamatis Rigas, Gerassimos E. Voutsinas, Popi Syntichaki
Format: | Article |
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Diterbitkan: | MDPI AG 2023-12-01 |
Deskripsi
p38 Mitogen-Activated Protein Kinase (MAPK) cascades are central regulators of numerous physiological cellular processes, including stress response signaling. In <i>C. elegans</i>, mitochondrial dysfunction activates a PMK-3/p38 MAPK signaling pathway (MAPK<sup>mt</sup>), but its functional role still remains elusive. Here, we demonstrate the induction of MAPK<sup>mt</sup> in worms deficient in the <i>lonp-1</i> 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<sup>mt</sup> and mitochondrial Unfolded Protein Response (UPR<sup>mt</sup>) surveillance pathways. Our results also reveal a genetic interaction in <i>lonp-1</i> 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 <i>lonp-1</i> animals, ZIP-2 is activated in a PMK-3-dependent manner but does not confer increased survival to pathogenic bacteria. However, deletion of <i>zip-2</i> or <i>pmk-3</i> shortens the lifespan of <i>lonp-1</i> mutants, suggesting a possible crosstalk under conditions of mitochondrial perturbation that influences the ageing process. Furthermore, loss of <i>pmk-3</i> specifically diminished the extreme heat tolerance of <i>lonp-1</i> worms, highlighting the crucial role of PMK-3 in the heat shock response upon mitochondrial LONP-1 inactivation.