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.

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Numerous small-molecule amines (SMAs) play critical roles in maintaining bone homeostasis and promoting bone regeneration regardless of whether they are applied as drugs or biomaterials. On the one hand, SMAs promote bone formation or inhibit bone resorption through the regulation of key molecular signaling pathways in osteoblasts/osteoclasts; on the other hand, owing to their alkaline properties as well as their antioxidant and anti-inflammatory features, most SMAs create a favorable microenvironment for bone homeostasis. However, due to a lack of information on their structure/bioactivity and underlying mechanisms of action, certain SMAs cannot be developed into drugs or biomaterials for bone disease treatment. In this review, we thoroughly summarize the current understanding of SMA effects on bone homeostasis, including descriptions of their classifications, biochemical features, recent research advances in bone biology and related regulatory mechanisms in bone regeneration. In addition, we discuss the challenges and prospects of SMA translational research.