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Dealing with physiological stress is a necessity for all organisms, and the pathways charged with this task are highly conserved in Metazoa . Accumulating evidence highlights cell-nonautonomous activation as an important mode of integrating stress responses at the organism level. Work in Caenorhabditis elegans highlighted the importance of such regulation for the unfolded protein response (UPR) and for gene expression downstream of the longevity-associated transcription factor DAF-16 Here we describe a role for the JNK homolog KGB-1 in cell-nonautonomous regulation of these two response modules. KGB-1 protects developing larvae from heavy metals and from protein folding stress (which we found to be independent of canonical UPR pathways), but sensitizes adults to the same stress, further shortening life span under normal conditions. This switch is associated with age-dependent antagonistic regulation of DAF-16 Using transgenic tissue-specific KGB-1 expression or tissue-specific KGB-1 activation we examined the contributions of KGB-1 to gene regulation, stress resistance, and life span. While cell-autonomous contributions were observed, particularly in the epidermis, cell-nonautonomous contributions of neuronal KGB-1 (and also in muscle) were effective in driving intestinal gene induction, age-dependent regulation of intestinal DAF-16, and stress resistance, and did not require KGB-1 expression in the target tissue. Additional genetic analyses revealed requirement for UNC-13 in mediating neuronal contributions, indicating involvement of neurotransmission. Our results expand the role of KGB-1 in stress responses from providing local cellular protection to integrating stress responses at the level of the whole organism.

The mitochondrial unfolded protein response (UPRmt) can be triggered in a cell-non-autonomous fashion across multiple tissues in response to mitochondrial dysfunction. The ability to communicate information about the presence of mitochondrial stress enables a global response that can ultimately better protect an organism from local mitochondrial challenges. We find that animals use retromer-dependent Wnt signaling to propagate mitochondrial stress signals from the nervous system to peripheral tissues. Specifically, the polyQ40-triggered activation of mitochondrial stress or reduction of cco-1 (complex IV subunit) in neurons of C. elegans results in the Wnt-dependent induction of cell-non-autonomous UPRmt in peripheral cells. Loss-of-function mutations of retromer complex components that are responsible for recycling the Wnt secretion-factor/MIG-14 prevent Wnt secretion and thereby suppress cell-non-autonomous UPRmt. Neuronal expression of the Wnt ligand/EGL-20 is sufficient to induce cell-non-autonomous UPRmt in a retromer complex-, Wnt signaling-, and serotonin-dependent manner, clearly implicating Wnt signaling as a strong candidate for the "mitokine" signal.