The Mitochondrial Unfolded Protein Response Is Mediated Cell-Non-autonomously by Retromer-Dependent Wnt Signaling

Abstract

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.

Mitochondrial translation and dynamics synergistically extend lifespan inC. elegansthrough HLH-30

“…Fragmenting mitochondrial structure by RNAi ablation of either eat-3 or fzo-1 stimulated the UPR MT (Fig. S2, A and B), consistent with recent findings (Zhang et al, 2018). Furthermore, mrps-5;eat-3 double RNAi triggered the strongest UPR MT response consistent with its most prominent lifespan increase, thus supporting our hypothesis ( Fig.…”

Do You Remember Mitochondria?

“…These observations lead to the formulation of the "mitohormesis" theory, in which a mild and sub-lethal mitochondrial stress activates a broad and complex cytosolic and nuclear response (Figure 1), able to promote long-lasting metabolic and biochemical changes, and to improve health and viability (Tapia, 2006;Yun and Finkel, 2014;Barcena et al, 2018). Key players in this scenario are mitochondria generated/released molecules, such as mtROS and mitokines, the role and nature of the latter still to be fully addressed (Durieux et al, 2011;Deng and Haynes, 2016;Zhang et al, 2018;Conte et al, 2019;Klaus and Ost, 2020), able FIGURE 1 | Reactive oxygen species promote health and lifespan. (A) Multiple mitochondria converging stresses results in an increased production of mitochondrial reactive oxygen species (mtROS), which are able to activate a transcriptional retrograde response, between the organelle and the nucleus, linking mtROS to nuclear events.…”

Axin-mediated regulation of lifespan and muscle health inC. elegansinvolves AMPK-FOXO signaling

“…When pry-1 was knocked down in mom-2(or42) and cwn-2(ok895) backgrounds, lifespan extension was significantly reduced in mom-2 mutants (13.6% reduction in mean lifespan, Figure 3A; Table S2) but remained unchanged in the cwn-2 animals ( Figure 3B; Table S2). We also analyzed the requirements of bar-1/β-catenin, a component of the canonical WNT signaling that plays a role in aging Zhang et al, 2018), in the mom-2-pry-1 pathway. Since pry-1-mediated WNT signaling negatively regulates bar-1, removing bar-1 function is expected to suppress the phenotype of pry-1 mutants.…”