Untersuchungen zur Rolle des mitochondrialen CLPXP Komplexes bei der Proteinqualitätskontrolle, Alterung und Entwicklung von Podospora anserina
Biochemie und Biophysik der Pflanzen
Zusammenfassung der Projektergebnisse
Organismic aging is known to be controlled by genetic and environmental traits. Pathways involved in the control of cellular metabolism play a crucial role. Previously, we identified a role of PaCLPP, a mitochondrial matrix protease, in the control of the mitochondrial energy metabolism, aging and lifespan of the fungal aging model Podospora anserina. Most surprisingly, we made the counterintuitive observation that the ablation of this component of the mitochondrial quality control network leads to lifespan extension. We now investigated the role of energy metabolism of P. anserina. In the PaClpP deletion mutant respiration via cytochrome c oxidase is maintained functional for a longer period within the lifetime. Moreover, our results indicate a critical role of acetyl-CoA depletion in autophagy-induction and lifespan extension. An age-dependent metabolome analysis of the wild-type and a PaClpP deletion strain verified differences and changes of various metabolites in cultures of the PaClpP mutant and the wild type. Based on these data we generated and analyzed a PaSnf1 deletion mutant and a DPaSnf1/DPaClpP double mutant. In both mutants PaSNF1, the catalytic a-subunit of AMP-activated protein kinase (AMPK) is ablated. PaSNF1 was found to be required for the development of fruiting bodies and ascospores, the progeny of sexual reproduction of this ascomycete, and impacts mitochondrial dynamics and autophagy. Most interestingly, while the single PaSnf1 deletion mutant is characterized by a slight lifespan increase, simultaneous deletion of PaSnf1 and PaClpP leads to a pronounced lifespan extension. This synergistic effect is strongly reinforced in the presence of the mating-type “minus”-linked allele of the rmp1 gene. Overall, our study identified novel interactions of different molecular pathways in the complex network involved in mitochondrial quality control, gene expression, and energy metabolism in the control of organismic aging.
Projektbezogene Publikationen (Auswahl)
- (2016) Orchestrating the network of molecular pathways affecting aging: Role of nonselective autophagy and mitophagy. Mech Ageing Dev 153: 30-40
Knuppertz L, Osiewacz HD
(Siehe online unter https://doi.org/10.1016/j.mad.2016.01.003) - (2017) Autophagy compensates impaired energy metabolism in CLPXP-deficient Podospora anserina strains and extends healthspan. Aging Cell 16: 704-715
Knuppertz L, Osiewacz HD
(Siehe online unter https://doi.org/10.1111/acel.12600) - (2021) Simultaneous ablation of the catalytic AMPK a-subunit SNF1 and mitochondrial matrix protease CLPP results in pronounced lifespan extension. Front Cell Dev Biol
Heinz D, Krotova E, Hamann A, Osiewacz HD
(Siehe online unter https://doi.org/10.3389/fcell.2021.616520)
