The PMK-3 (p38) Mitochondrial Retrograde Response Functions in Intestinal Cells to Extend Life via the ESCRT Machinery

Abstract

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 2 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. Abbreviations: C/EBPβ, CCAAT/enhancer binding protein β ; DLK-1b(EE), constitutively active form of DLK-1 isoform b; ESCRT-III, endosomal sorting complexes required for transport type III complex;ETC, electron transport chain; EVs, extracellular vesicles (exosomes and exosomes); MAPK, mitogenactivated protein kinase; Ptbb-6::GFP, GFP coupled to the promoter of tbb-6 3 gene expression changes to resolve or reduce mitochondrial stress. Higher eucaryotes have evolved different kinds of retrograde responses that are triggered by a variety of stressors, including protein aggregation (8), changes in ETC activity (9), oxidative stress (10) and loss of iron (11). One innovative approach to countering age-related decline of mitochondrial function is to exploit retrograde responses to prophylactically protect, or even rejuvenate, the mitochondrial network. Retrograde responses might therefore represent an untapped means by which to potentially ameliorate multiple age-related diseases simultaneously.Responses that counteract mitochondrial ETC disruption have been most extensively studied in the nematode Caenorhabditis elegans (9, 12-16). Several years ago, we showed that the response of C.elegans to mitochondrial ETC dysfunction is threshold-dependent. That is, low levels of stress produce no phenotype, moderate levels increase lifespan, while severe disruption, as in humans, leads to overt pathology and shortened lifespan (13). Recently, we described a novel retrograde response in C. elegans that extended life and did not overlap with known longevity-promoting pathways (17). This retrograde response operates independently of the well-characterized ATFS-1-dependent mitochondrial unfolded protein response (18), the NRF2/SKN-1-dependent...

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