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...
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| Language: | English |
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MDPI AG
2023-12-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/24/17209 |
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| author | Eirini Taouktsi Eleni Kyriakou Evangelia Voulgaraki Dimitris Verganelakis Stefania Krokou Stamatis Rigas Gerassimos E. Voutsinas Popi Syntichaki |
| author_facet | Eirini Taouktsi Eleni Kyriakou Evangelia Voulgaraki Dimitris Verganelakis Stefania Krokou Stamatis Rigas Gerassimos E. Voutsinas Popi Syntichaki |
| author_sort | Eirini Taouktsi |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-08T20:41:48Z |
| format | Article |
| id | doaj.art-5e6aba55f9a04c86b6bb81c02aac65b2 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-08T20:41:48Z |
| publishDate | 2023-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-5e6aba55f9a04c86b6bb81c02aac65b22023-12-22T14:13:37ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-12-0124241720910.3390/ijms242417209Mitochondrial p38 Mitogen-Activated Protein Kinase: Insights into Its Regulation of and Role in LONP1-Deficient NematodesEirini Taouktsi0Eleni Kyriakou1Evangelia Voulgaraki2Dimitris Verganelakis3Stefania Krokou4Stamatis Rigas5Gerassimos E. Voutsinas6Popi Syntichaki7Laboratory of Molecular Genetics of Aging, Biomedical Research Foundation of the Academy of Athens, Center of Basic Research, 11527 Athens, GreeceLaboratory of Molecular Genetics of Aging, Biomedical Research Foundation of the Academy of Athens, Center of Basic Research, 11527 Athens, GreeceLaboratory of Molecular Genetics of Aging, Biomedical Research Foundation of the Academy of Athens, Center of Basic Research, 11527 Athens, GreeceLaboratory of Molecular Genetics of Aging, Biomedical Research Foundation of the Academy of Athens, Center of Basic Research, 11527 Athens, GreeceLaboratory of Molecular Genetics of Aging, Biomedical Research Foundation of the Academy of Athens, Center of Basic Research, 11527 Athens, GreeceDepartment of Biotechnology, Agricultural University of Athens, 11855 Athens, GreeceLaboratory of Molecular Carcinogenesis and Rare Disease Genetics, Institute of Biosciences and Applications, National Center for Scientific Research “Demokritos”, Aghia Paraskevi Attikis, 15341 Athens, GreeceLaboratory of Molecular Genetics of Aging, Biomedical Research Foundation of the Academy of Athens, Center of Basic Research, 11527 Athens, Greecep38 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.https://www.mdpi.com/1422-0067/24/24/17209mitochondriaageingheat stress response<i>C. elegans</i>LONP-1PMK-3 |
| spellingShingle | Eirini Taouktsi Eleni Kyriakou Evangelia Voulgaraki Dimitris Verganelakis Stefania Krokou Stamatis Rigas Gerassimos E. Voutsinas Popi Syntichaki Mitochondrial p38 Mitogen-Activated Protein Kinase: Insights into Its Regulation of and Role in LONP1-Deficient Nematodes International Journal of Molecular Sciences mitochondria ageing heat stress response <i>C. elegans</i> LONP-1 PMK-3 |
| title | Mitochondrial p38 Mitogen-Activated Protein Kinase: Insights into Its Regulation of and Role in LONP1-Deficient Nematodes |
| title_full | Mitochondrial p38 Mitogen-Activated Protein Kinase: Insights into Its Regulation of and Role in LONP1-Deficient Nematodes |
| title_fullStr | Mitochondrial p38 Mitogen-Activated Protein Kinase: Insights into Its Regulation of and Role in LONP1-Deficient Nematodes |
| title_full_unstemmed | Mitochondrial p38 Mitogen-Activated Protein Kinase: Insights into Its Regulation of and Role in LONP1-Deficient Nematodes |
| title_short | Mitochondrial p38 Mitogen-Activated Protein Kinase: Insights into Its Regulation of and Role in LONP1-Deficient Nematodes |
| title_sort | mitochondrial p38 mitogen activated protein kinase insights into its regulation of and role in lonp1 deficient nematodes |
| topic | mitochondria ageing heat stress response <i>C. elegans</i> LONP-1 PMK-3 |
| url | https://www.mdpi.com/1422-0067/24/24/17209 |
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