Ferritin-mediated iron detoxification promotes hypothermia survival in Caenorhabditis elegans and murine neurons

Pekeč, Tina; Lewandowski, Jarosław; Komur, Alicja A.; Sobańska, Daria; Guo, Yanwu; Świtońska-Kurkowska, Karolina; Małecki, Jędrzej; Dubey, Abhishek Anil; Pokrzywa, Wojciech; Frankowski, Marcin; Figiel, Maciej; Ciosk, Rafal

doi:10.1038/s41467-022-32500-z

Cited by 9 publications

(11 citation statements)

References 97 publications

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“…C. elegans tightly regulates iron homeostasis through the control of iron transporter SMF-3, as well as the regulation of iron storage protein Ferritins FTN-1 and FTN-2 (Cha’on et al, 2007; Gourley, Parker, Jones, Zumbrennen, & Leibold, 2003; Kim, Cho, Yoo, & Ahnn, 2004; Pekec et al, 2022). Among the most differentially regulated genes, ftn-1 appeared to be consistently downregulated by H 2 S ( Figure 5A and B, Figure 5—figure supplement 1A–D ).…”

Section: Resultsmentioning

confidence: 99%

Acute avoidance of hydrogen sulfide is modulated by external and internal states inC. elegans

Pu,

Zhao,

Wang

et al. 2023

Preprint

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Hydrogen sulfide (H2S) can act as an energy source, a poison and a gasotransmitter in organisms. We used the robust locomotory responses to H2S inCaenorhabditis elegansto delineate the molecular mechanisms governing sensory and adaptive responses to H2S exposure. We found thatC. elegansexhibited transiently increased locomotory activity and turning behavior as a strategy to escape the noxious H2S stimulation. The behavioral responses to H2S were modulated by a complex network of signaling pathways, including cyclic GMP signaling in ciliated sensory neurons, calcineurin, nuclear hormone receptors, to the major starvation regulators such as insulin and TGF-β signaling. The response to H2S was substantially affected by the ambient O2levels and their prior experience in low O2environments, suggesting an intricate interplay between O2and H2S sensing mechanisms. Prolonged exposure to H2S robustly evoked H2S detoxification coupled with reduced locomotory response to the subsequent H2S challenges. Intriguingly, the expression of genes involved in iron homeostasis, includingftn-1andsmf-3, was substantially modified in exposure to H2S, implying that labile iron levels are affected by H2S. In support of this, iron supplement significantly bolstered the behavioral response to H2S. In addition, mitochondria, one of the central hubs for H2S metabolism, played a crucial role in adaptive responses to H2S. In summary, our study provides molecular insights into the mechanisms through whichC. elegansdetects, modulates, and adapts its response to H2S.

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Section: Resultsmentioning

confidence: 99%

Acute avoidance of hydrogen sulfide is modulated by external and internal states inC. elegans

Pu,

Zhao,

Wang

et al. 2023

Preprint

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“…Our results suggest that, although PQM-1 nuclear exclusion by DAF-16 occurs only in daf-2 mutants but not under wild-type conditions, ETS-4 nuclear localization is hindered by DAF-16 even under wild-type conditions. ( Fig 3D , [ 6 , 23 ]).…”

Section: Resultsmentioning

confidence: 99%

“…ETS-4 contains both an ETS DNA binding domain and a PNT domain. Previous studies have shown that deleting ets-4 leads to a longer lifespan and increased cold tolerance [ 23 , 24 ]. However, ETS-4 is not always associated with negative effects in C .…”

Section: Introductionmentioning

confidence: 99%

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Rege-1 promotes C. elegans survival by modulating IIS and TOR pathways

Tsai,

Chang,

Tsai

2023

PLoS Genet

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Metabolic pathways are known to sense the environmental stimuli and result in physiological adjustments. The responding processes need to be tightly controlled. Here, we show that upon encountering P. aeruginosa, C. elegans upregulate the transcription factor ets-4, but this upregulation is attenuated by the ribonuclease, rege-1. As such, mutants with defective REGE-1 ribonuclease activity undergo ets-4-dependent early death upon challenge with P. aeruginosa. Furthermore, mRNA-seq analysis revealed associated global changes in two key metabolic pathways, the IIS (insulin/IGF signaling) and TOR (target of rapamycin) kinase signaling pathways. In particular, failure to degrade ets-4 mRNA in activity-defective rege-1 mutants resulted in upregulation of class II longevity genes, which are suppressed during longevity, and activation of TORC1 kinase signaling pathway. Genetic inhibition of either pathway way was sufficient to abolish the poor survival phenotype in rege-1 worms. Further analysis of ETS-4 ChIP data from ENCODE and characterization of one upregulated Class II gene, ins-7, support that the Class II genes are activated by ETS-4. Interestingly, deleting an upregulated Class II gene, acox-1.5, a peroxisome β-oxidation enzyme, largely rescues the fat lost phenotype and survival difference between rege-1 mutants and wild-types. Thus, rege-1 appears to be crucial for animal survival due to its tight regulation of physiological responses to environmental stimuli. This function is reminiscent of its mammalian ortholog, Regnase-1, which modulates the intestinal mTORC1 signaling pathway.

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“…It is noteworthy that the beneficial effects of FUdR in promoting worms survival and protein turnover are not dependent on evolutionarily preserved transcriptional regulators DAF-13 16 and PQM-1, recognized for their cooperative role in enhancing resilience to cold conditions through the upregulation of FTN-1/ferritin (53). This delineates a distinct mechanistic route through which FUdR modulates cellular homeostasis and also raises intriguing questions about the potential cross-talk between various stress response pathways and how they might be selectively activated or bypassed.…”

Section: Discussionmentioning

confidence: 99%

Sterility-Independent Enhancement of Proteasome Function via Floxuridine-Triggered Detoxification inC. elegans

Dubey,

Szulc,

Piechota

et al. 2023

Preprint

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The ubiquitin-proteasome system (UPS) functionality is vital for proteostasis, contributing to stress resilience, lifespan, and thermal adaptability. InCaenorhabditis elegans, proteasome constituents such as the RPN-6 and PBS-6 subunits or the PSME-3 activator are respectively linked to heat resistance, survival at low temperatures (4°C), and longevity at moderate cold (15°C). Since the inhibition of germline stem cells proliferation is associated with robust proteostasis in worms, we utilized floxuridine (FUdR), a compound known for inducing sterility, to examine whether it could reinforce UPS under proteasome dysfunction, particularly to foster cold survival. We demonstrate that FUdR promotes proteasome resilience during its inhibition or subunit deficits, supporting normal lifespan and facilitating adaptation to cold. FUdR’s elevation of the UPS activity occurs independently of main proteostasis regulators and is partly driven by SKN-1-regulated transcription, especially under reduced proteasome function. Additionally, we uncover a FUdR-stimulated detoxification pathway, distinct from both SKN-1 and the germline, with GST-24 emerging as a critical mediator of the UPS buffering. This research underscores FUdR’s role in the UPS modulation and its contribution to survival of worms in low-temperature conditions.HIGHLIGHTSFloxuridine (FUdR) enhances ubiquitin-proteasome system activity inC. elegans, independent of primary proteostasis regulators.FUdR permits worms to maintain a normal lifespan and facilitates their adaptation to cold in the context of proteasome deficits.Acting independently of the germline and SKN-1, FUdR triggers a detoxification pathway, with GST-24 as a pivotal component in modulating the ubiquitin-proteasome system.

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Ferritin-mediated iron detoxification promotes hypothermia survival in Caenorhabditis elegans and murine neurons

Cited by 9 publications

References 97 publications

Acute avoidance of hydrogen sulfide is modulated by external and internal states inC. elegans

Acute avoidance of hydrogen sulfide is modulated by external and internal states inC. elegans

Rege-1 promotes C. elegans survival by modulating IIS and TOR pathways

Sterility-Independent Enhancement of Proteasome Function via Floxuridine-Triggered Detoxification inC. elegans

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