RT Journal Article
SR Electronic
T1 The PMK-3 (p38) Mitochondrial Retrograde Response Functions in Intestinal Cells to Extend Life via the ESCRT Machinery
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 797308
DO 10.1101/797308
A1 Oxana Radetskaya
A1 Rebecca K. Lane
A1 Troy Friedman
A1 Aria Garrett
A1 Megan B. Borror
A1 Joshua Russell
A1 Shane L. Rea
YR 2019
UL http://biorxiv.org/content/early/2019/10/08/797308.abstract
AB The p38 mitogen-activated protein kinase (MAPK) PMK-3 controls a life-extending retrograde response in the nematode Caenorhabditis elegans that is activated following mitochondrial electron transport chain (ETC) disruption and is distinct from known longevity-promoting pathways. Here we show that the long isoform of PMK-3 expressed exclusively in the gut, rather than neurons, is sufficient to fully extend the life of animals exposed to mild ETC dysfunction. Surprisingly, constitutive activation of PMK-3 using a gain-of-function MAP3K/DLK-1 mutant does not extend the life of wild-type worms due to dampening of the DLK-1/PMK-3 signaling axis with age. We further show that core components of the ESCRT-III machinery, including ISTR-1, CHMP2B (CC01A4.2) and RAB-11.1, are required for life extension following ETC disruption. ESCRT proteins are needed for extracellular vesicle (EV) formation, lysosomal traffic and other functions requiring membrane encapsulation away from the cytoplasm. Together, our findings underscore PMK-3 as a pivotal factor controlling life extension in worms following mitochondrial ETC disruption and illustrate the importance of the endomembrane system to this process. Our findings raise the possibility that EVs may act as intra-organismal signaling vehicles to control aging.C/EBPβCCAAT/enhancer binding protein βDLK-1b(EE)constitutively active form of DLK-1 isoform bESCRT-IIIendosomal sorting complexes required for transport type III complexETCelectron transport chainEVsextracellular vesicles (exosomes and exosomes)MAPKmitogen-activated protein kinasePtbb-GFP∷6GFP coupled to the promoter of tbb-6