DLK-1, SEK-3 and PMK-3 Are Required for the Life Extension Induced by Mitochondrial Bioenergetic Disruption in C. elegans

Abstract

Mitochondrial dysfunction underlies numerous age-related pathologies. In an effort to uncover how the detrimental effects of mitochondrial dysfunction might be alleviated, we examined how the nematode C. elegans not only adapts to disruption of the mitochondrial electron transport chain, but in many instances responds with extended lifespan. Studies have shown various retrograde responses are activated in these animals, including the well-studied ATFS-1-dependent mitochondrial unfolded protein response (UPRmt). Such processes fall under the greater rubric of cellular surveillance mechanisms. Here we identify a novel p38 signaling cascade that is required to extend life when the mitochondrial electron transport chain is disrupted in worms, and which is blocked by disruption of the Mitochondrial-associated Degradation (MAD) pathway. This novel cascade is defined by DLK-1 (MAP3K), SEK-3 (MAP2K), PMK-3 (MAPK) and the reporter gene Ptbb-6::GFP. Inhibition of known mitochondrial retrograde responses does not alter induction of Ptbb-6::GFP, instead induction of this reporter often occurs in counterpoint to activation of SKN-1, which we show is under the control of ATFS-1. In those mitochondrial bioenergetic mutants which activate Ptbb-6::GFP, we find that dlk-1, sek-3 and pmk-3 are all required for their life extension.

Lactate and pyruvate promote cellular stress resistance and longevity through ROS signaling

“…is known to regulate longevity induced by mitochondrial disruption and axonal regeneration pathways 50,51 , consistent with our overall observations in cells and the ROS induction observed in the nematode. However, knockdown of pmk-3 canonical upstream control dlk-1 did not influence lactate-or pyruvate-mediated stress resistance ( Supplementary Fig.…”

BRCA 1 and BARD 1 mediate apoptotic resistance but not longevity upon mitochondrial stress in Caenorhabditis elegans

“…Changes in animal metabolism, the induction of protective and detoxifying systems (e.g., mtUPR, antioxidants, autophagy) [7,[13][14][15][16], a smaller germline, a decreased but prolonged fertility, and a reduced adult size (often accompanied by slower development) are all associated with lifespan extension upon mitochondrial disturbance. Moreover, different molecular players have been identified in the past two decades that mediate Mit mutants' longevity: a handful of transcription factors [7,[17][18][19][20][21][22], autophagy-and apoptosis-regulatory genes [7,14,18,23,24], some kinases [25][26][27], as well as some mitochondrial metabolites [28] and chromatin remodeling genes [29,30]. Nonetheless, whether the same molecular mechanisms underlie the different Mit-mutant's phenotypic features is largely unknown [14,31,32].…”

Inhibition of ATR Reverses a Mitochondrial Respiratory Insufficiency

“…This model reflects the well-established redundancy in the DNA damage response network 22 . Several recent studies by us and others 13, 36, 37 , have shown a role for MAPK signaling following ETC disruption in worms. Interestingly, the p38 MAPK-activated protein kinases MAPKAP-2 and MAPKAP-3 are checkpoint proteins known in humans to act in parallel to ATM and ATR 38, 39, 40 .…”

“…We next tested whether loss of atl-1 affected the activity of major stress response pathways known to be activated by atp-3 or isp-1 depletion 3, 13, 35, 56 . Loss of atl-1 did not result in constitutive activation of P hsp-6::GFP , P gst-4::GFP or P tbb-6::GFP , which are markers of ATFS-1, SKN-1/NRF-2 and PMK-3/p38 activation, respectively ( Supplemental Fig.…”

“…For example, an increase in the unfolded protein load of the mitochondrial matrix re-directs the transcription factor ATFS-1 from the matrix to the nucleus where it stimulates expression of mitochondrial chaperones 11 . Other signals such as changes in calcium concentration, activation of mitogen-activated protein kinases (MAPKs), and even knock-on changes in the cytoplasmic unfolded protein load, also result in retrograde response activation 12, 13, 14 . Counter-measures that are activated by cells include increased mitochondrial biogenesis, elevated mitochondrial DNA (mtDNA) replication, increased mitophagy, activation of alternate pathways of energy production (such as glycolysis), and changes in the abundance and activity of respiratory complexes or their regulatory factors 8, 15, 16 .…”