The regulation of mitochondrial fusion to extend longevity and the exogenous regulation of germ cell proliferation in caenorhabtidis elegans
Chaudhari, Snehal Nitin
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Mitochondria are dynamic organelles that undergo fusion and fission events in all eukaryotic cells. Mitochondrial dynamics are required for mitochondrial viability and serve as indicators of cellular health and bioenergetic status. Here we describe a pathway that regulates mitochondrial fusion in the nematode Caenorhabditis elegans. In this pathway, the ubiquitin ligase SCFLIN-23 and its exchange factor CAND-1 promote the activity of the AKT-1 kinase, which inactivates the FOXO transcription factor DAF-16. DAF-16 represses the expression of the mitochondrial proteases SPG-7 and PPGN-1, which inhibit the mitochondrial fusion protein EAT-3. Altering components of the pathway to increase mitochondrial fusion is associated with increased lifespan. We further show that diverse long-lived C. elegans mutants exhibit increased mitochondrial fusion, and that the fusion is essential for their longevity. Interestingly, physical exertion in C. elegans induces mitochondrial fusion, which requires DAF-16 activity. Furthermore, a daily exercise regimen in C. elegans extends lifespan by 60% compared to animals that are not subjected to exercise. Overall, these results demonstrate the regulation and importance of mitochondrial fusion in physical exertion and longevity. C. elegans germ cells are syncytial and cannot be isolated and cultured. However, the germ cells from tumorous mutants can be cellularized and isolated from the animals, and cultured. Using this culture system, we found that the steroid hormone dafachronic acid inhibits C. elegans germ cell proliferation in vitro and in vivo, and requires the steroid hormone receptor DAF-12 for this function. We also identified bacterial folates as positive regulators of germ cell proliferation. Folates are B-complex vitamins that are required for the de novo synthesis of amino acids and nucleosides. We show that a bacterial folate – 10-formyl-tetrahydrofolate-Glun – signals germ cells to proliferate in vitro and in vivo. The bacterial folate precursor dihydropteroate also promotes germ cell proliferation in vitro and in vivo, despite its inability to promote one-carbon metabolism. The folate receptor homolog FOLR-1 is required for the stimulation of germ cells by 10-formyl-tetrahydrofolate-Glun and dihydropteroate.