Mitochondrial p38 Mitogen-Activated Protein Kinase: Insights into Its Regulation of and Role in LONP1-Deficient Nematodes
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...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-12-01
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| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/24/24/17209 |
| Summary: | 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. |
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| ISSN: | 1661-6596 1422-0067 |