Neuronal HLH‐30/TFEB modulates peripheral mitochondrial fragmentation to improve thermoresistance in Caenorhabditis 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 processes, we investigated the role of neuronal TFEB in stress resistance and longevity. To this end, the Caenorhabditis elegans TFEB ortholog, 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/TFEB 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 wildtype but not daf‐2 animals. Notably, these mechanisms can be uncoupled, as neuronal HLH‐30/TFEB requires DAF‐16/FOXO to regulate longevity but not thermoresistance. Through further transcriptomics profiling and functional analysis, we discovered that neuronal HLH‐30/TFEB modulates neurotransmission through the hitherto uncharacterized protein W06A11.1 by inducing peripheral mitochondrial fragmentation and organismal heat stress resistance in a non‐cell autonomous manner. Taken together, this study uncovers a novel mechanism of heat stress protection mediated by neuronal HLH‐30/TFEB.