Abstract
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. In the current study, we investigated the role of energy metabolism of P. anserina. 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 ΔPaSnf1/ΔPaClpP double mutant. In both mutants PaSNF1, the catalytic α-subunit of AMP-activated protein kinase (AMPK) is ablated. PaSNF1 was found to be required for the development of fruiting bodies and ascospores and the progeny of sexual reproduction of this ascomycete and impact 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. Compared to the wild type, culture temperature of 35°C instead of the standard laboratory temperature of 27°C leads to a short-lived phenotype of the ΔPaSnf1/ΔPaClpP double mutant. Overall, our study provides novel evidence for complex interactions of different molecular pathways involved in mitochondrial quality control, gene expression, and energy metabolism in the control of organismic aging.
Highlights
Aging of biological systems is characterized by a time-dependent decrease of physiological functions and an increase in morbidity and mortality
The deletion of the gene coding for PaIAP, an AAA protease (ATPases associated with diverse cellular activities) that is located in the inner mitochondrial membrane, was found to lead to a lifespan extension (Weil et al, 2011)
The previous demonstration of potential substrates of the mitochondrial PaCLPXP complex, the majority of which are associated with metabolic pathways in mitochondria (Fischer et al, 2015b), and the observation that the ablation of the protease and chaperone component of the complex leads to a pronounced lifespan extension (Fischer et al, 2013) directed our interest to more carefully investigate the impact of metabolic processes on aging of P. anserina
Summary
Aging of biological systems is characterized by a time-dependent decrease of physiological functions and an increase in morbidity and mortality It has a multifactorial basis, and various molecular pathways are known to control aging, lifespan, and healthspan. It was shown that the overexpression of the gene coding for the mitochondrial LON protease leads to a healthspan extension via the increased degradation of damaged (carbonylated) proteins and the conservation of mitochondrial function (Luce and Osiewacz, 2009). While such an effect was expected, results from some other experimental interventions were counterintuitive and unexpected. There are components of the N-module of respiratory complex I which were subsequently identified in mammals and the plant Arabidopsis thaliana (Szczepanowska et al, 2016; Petereit et al, 2020) suggesting at least a partial conserved role of CLPXP in pathways involved in cellular energy metabolism
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