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Transgenerational inheritance of increased mtDNA triggers mitochondrial UPR and modulates aging [WT vs. TGQ]

ABSTRACT: It would be evolutionarily beneficial if the information of transient stresses experienced by parents could be passed on to descendants as a forecast of the challenges to come. Here, we discovered that neuronal mitochondrial perturbations can transmit the mitochondrial unfolded protein response (UPRmt) to offspring for multiple generations in Caenorhabditis elegans. The transgenerational induction of UPRmt was caused by a higher level of maternally inherited mitochondrial DNA (mtDNA), which disturbed the balance of oxidative phosphorylation subunits encoded by mtDNA and nuclear DNA. Furthermore, an increase in mtDNA levels requires Wnt/b-catenin signaling to propagate across generations, thereby inducing the UPRmt and conferring increased lifespan and stress tolerance. Thus, transgenerational increase in mtDNA levels and the UPRmt enable offspring to live longer and confer stress tolerance.

ORGANISM(S): Caenorhabditis elegans

PROVIDER: GSE157031 | GEO | 2021/06/22

REPOSITORIES: GEO

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Project description:Damage to the mitochondrial genome (mtDNA) severely affects the cell and causes disease. Mutations to mtDNA also accumulate throughout the lifespan of many organisms and may be a proximal cause of aging. There is no effective treatment for ailments caused by mtDNA mutation. Since mitochondrial function and biogenesis are controlled by the nutrient environment of the cell, it is possible that perturbation of conserved, nutrient-sensing pathways may successfully treat mitochondrial disease. Experiments using the tractable eukaryote Saccharomyces cerevisiae allow us to investigate the connection between nutrient-sensing and mitochondrial function. We have focused our current studies on the protein kinase A (PKA) pathway, which controls S. cerevisiae behavior according to glucose availability. We found that reduced PKA signaling can lead, in a background-dependent manner, to improved fitness after mtDNA loss. Specifically, over-expression of the cyclic AMP phosphodiesterase Pde2p, removal of PKA isoform Tpk3p, or ablation of other proteins promoting PKA activity leads to improved proliferation of cells deleted of the mitochondrial genome. Over-expression of Pde2p also suppresses the inviability of several mutants that normally cannot survive mtDNA loss. Moreover, Pde2p over-expression diminishes the nuclear transcriptional response to mtDNA damage, further supporting the idea that glucose sensation is harmful for cells lacking the mitochondrial genome. These findings are heavily dependent upon yeast genetic background. Interestingly, robust import of mitochondrial polytopic membrane proteins may be required in order for cells with no mtDNA to receive the full benefits of PKA reduction. Our findings support the idea that perturbation of nutrient-sensing pathways, and specifically the sensation of glucose, may benefit cells with dysfunctional mitochondria. Four experimental conditions were used: BY4743 (WT) cells containing empty pRS426 vector and containing mtDNA because EtBr was not used, BY4743 (WT) cells containing empty pRS426 vector and lacking mtDNA after 24 hours of treatment with 25 µg/ml ethidium bromide, BY4743 (WT) cells overexpressing TIP41 from plasmid pRS426 and lacking mtDNA after 24 hours of treatment with 25 µg/ml ethidium bromide, and BY4743 (WT) cells overexpressing PDE2 from plasmid pRS426 and lacking mtDNA after 24 hours of treatment with 25 µg/ml ethidium bromide. Two replicates were performed for each sample type.

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Transgenerational inheritance of increased mtDNA triggers mitochondrial UPR and modulates aging [WT vs. TGQ]

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