Neuronal HLH-30/TFEB modulates muscle mitochondrial fragmentation to improve thermoresistance in C. elegans

Transcription factor EB (TFEB) is a conserved master transcriptional activator of autophagy and lysosomal genes that modulates organismal lifespan regulation and stress resistance. As neurons can coordinate organism-wide mechanisms, we investigated the role of neuronal TFEB in stress resistance and longevity. To this end, the C. elegans TFEB orthologue, hlh-30, was rescued panneuronally in hlh-30 loss of function mutants. While important in the long lifespan of daf-2 animals, neuronal hlh-30 was not sufficient to restore normal lifespan in short-lived hlh-30 mutants. However, neuronal HLH-30/TFEB rescue mediated robust improvements in the heat stress resistance of wild-type but not daf-2 animals. Notably, these mechanisms can be uncoupled, as neuronal HLH-30/TFEB regulates longevity and thermoresistance dependently and independently of DAF-16/FOXO respectively. Through transcriptomics profiling and functional analysis, we identified the uncharacterized gene W06A11.1 as a bona fide mediator of heat stress resistance via the induction of mitochondrial fragmentation in distal muscles. Neuron-to-muscle communication occurred through a modulation of neurotransmission. Taken together, this study uncovers a novel mechanism of heat stress protection mediated by neuronal HLH-30/TFEB.