The mitochondrial unfolded protein response (UPR) 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 UPR 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 UPR. Neuronal expression of the Wnt ligand/EGL-20 is sufficient to induce cell-non-autonomous UPR in a retromer complex-, Wnt signaling-, and serotonin-dependent manner, clearly implicating Wnt signaling as a strong candidate for the "mitokine" signal.

Wnt/Wingless signal transduction directs fundamental developmental processes, and upon hyperactivation triggers colorectal adenoma/carcinoma formation. Responses to Wnt stimulation are cell specific and diverse; yet, how cell context modulates Wnt signalling outcome remains obscure. In a Drosophila genetic screen for components that promote Wingless signalling, we identified Earthbound 1 (Ebd1), a novel member in a protein family containing Centromere Binding Protein B (CENPB)‐type DNA binding domains. Ebd1 is expressed in only a subset of Wingless responsive cell types, and is required for only a limited number of Wingless‐dependent processes. In addition, Ebd1 shares sequence similarity and can be functionally replaced with the human CENPB domain protein Jerky, previously implicated in juvenile myoclonic epilepsy development. Both Jerky and Ebd1 interact directly with the Wnt/Wingless pathway transcriptional co‐activators β‐catenin/Armadillo and T‐cell factor (TCF). In colon carcinoma cells, Jerky facilitates Wnt signalling by promoting association of β‐catenin with TCF and recruitment of β‐catenin to chromatin. These findings indicate that tissue‐restricted transcriptional co‐activators facilitate cell‐specific Wnt/Wingless signalling responses by modulating β‐catenin–TCF activity.

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