In C. elegans, removal of the germline stem cells during early development results in lifespan extension in presence of somatic gonad. This longevity depends on autophagy and fat metabolism mediated by several transcription factors such as HLH-30/TFEB, NHR-80/HNF-4 and NHR-49/PPARa. However, little is known about the molecular links connecting these different pathways involved in gonadal longevity. Through RNAi-based genetic screening using
glp-1 mutants, we have identified that Mondo-like transcription factor MML-1 and its heterodimer partner MXL-2 are both required for gonadal longevity. Subsequent analysis implicated that MML-1/MXL-2 affect HLH-30 nuclear localization, its target gene expression and downstream processes such as autophagy are impaired in germline deficient
mml-1 and
mxl-2 mutants. This phenotype is partially caused by the hyperactivation of TOR, since downregulation of TOR pathway rescued HLH-30 nuclear localization phenotype and its downstream target gene expression. A recent study by Folick et al., 2015 showed that oleoylethanolamide (OEA), produced by LIPL-4 and carried to nucleus by LBP-8, binds to NHR-80 resulting in the activation of NHR-80 and NHR-49 nuclear hormone receptors and thus longevity. Interestingly, we found that
lipl-4 and
lbp-8 transcript levels are decreased in germline deficient
mml-1 and
mxl-2 mutants, resulting in low levels of OEA as well as NHR-49 and NHR-80 target gene expression. These observations suggested that MML-1/MXL-2 regulate both TOR/HLH-30 axis and LIPL-4/OEA/NHR-80/NHR-49 axis. Our ongoing analysis will reveal the interconnectivity between these two axes through MML-1/MXL-2.