Soo, Sonja K et al. (2021) MicroPubl Biol

Van Raamsdonk, Jeremy M, Soo, Sonja K

[MicroPubl Biol, 2021]

The mitochondrial unfolded protein response (mitoUPR) is a stress response pathway that promotes cell survival and restores mitochondrial function when mitochondrial health is compromised (Haynes et al. 2013; Jovaisaite et al. 2014; Shpilka and Haynes 2018). While a mitoUPR was first reported in mammalian cells (Zhao et al. 2002), the initial work on the mitoUPR in C. elegans was performed by Yoneda et al. who found that treatment with ethidium bromide, which affects the replication and expression of mitochondrial DNA, increased the expression of the mitochondrial chaperone gene hsp-6 (Yoneda et al. 2004). Based on this observation, they generated hsp-6p::gfp and hsp-60p::gfp reporter strains to further study the mitoUPR. They found that either RNA interference (RNAi) targeting spg-7, the worm homolog of paraplegin, or RNAi targeting other genes encoding mitochondrial proteins resulted in activation of the hsp-6p::gfp and hsp-60p::gfp reporter strains (Yoneda et al. 2004).

Broadley SA et al. (2008) Trends Cell Biol "Mitochondrial stress signaling: a pathway unfolds."

Broadley SA, Hartl FU

[Trends Cell Biol, 2008]

Disruption of protein homeostasis in mitochondria elicits a cellular response, which upregulates mitochondrial chaperones and other factors that serve to remodel the mitochondrial-folding environment. In a recent study, Haynes and colleagues uncovered a novel signal transduction pathway underlying this process. The upstream mitochondrial component of this pathway is an orthologue of Escherichia coli ClpP, which functions in the bacterial heat-shock response. These findings suggest that molecular aspects of stress sensing might be conserved between bacteria and mitochondria.

Berry, Brandon J. et al. (2021) MicroPubl Biol

Wojtovich, Andrew P., Berry, Brandon J., Nieves, Tyrone O.

[MicroPubl Biol, 2021]

Mitochondria are organelles that make ATP by generating a proton gradient across the inner membrane through the action of the electron transport chain (ETC). The gradient is composed of a membrane potential (m) and a concentration gradient (pH). In addition to energy production, mitochondria are recognized as signaling organelles (Chandel 2015), and m powers diverse signaling outputs that mitochondria coordinate. One such signaling response is the mitochondrial unfolded protein response (UPRmt). Some ETC complex components are encoded by mitochondrial or nuclear genes and require coordination between the genomes for proper stoichiometry (Shpilka and Haynes 2018). The UPRmt is a protein homeostasis response that is activated when nuclear and mitochondrial gene expression are not correctly coordinated (Melber and Haynes 2018). When the expression of mitochondrial and nuclear encoded proteins is mismatched, the UPRmt is activated. In C. elegans, the UPRmt is controlled by the transcription factor ATFS-1, which is normally trafficked to mitochondria and degraded. When nuclear:mitochondrial gene expression is perturbed, ATFS-1 is blocked from entering mitochondria and is instead trafficked to the nucleus where a host of chaperones and stress-response genes are activated and transcribed.

Benedetti C et al. (2006) Genetics "Ubiquitin-like protein 5 positively regulates chaperone gene expression in the mitochondrial unfolded protein response."

Yang Y, Haynes C, Ron D, Harding HP, Benedetti C

[Genetics, 2006]

Perturbation of the protein folding environment in the mitochondrial matrix selectively upregulates the expression of nuclear genes encoding mitochondrial chaperones. To identify components of the signal transduction pathway(s) mediating this mitochondrial unfolded protein response (UPRmt) we first isolated a temperature sensitive mutation (zc32) that conditionally activates the UPRmt in C. elegans and subsequently searched for suppressors by systematic inactivation of genes. RNAi of ubl-5, a gene encoding an ubiquitin like protein, suppresses activation of the UPRmt markers hsp-60::gfp and hsp-6::gfp by the zc32 mutation and by other manipulations that promote mitochondrial protein misfolding. ubl-5 (RNAi) inhibits the induction of endogenous mitochondrial chaperone encoding genes hsp-60 and hsp-6 and compromises animals'' ability to cope with mitochondrial stress. Mitochondrial morphology and assembly of multi-subunit mitochondrial complexes of biotinylated proteins are also perturbed in ubl-5(RNAi) worms, indicating that UBL-5 also counteracts physiological levels of mitochondrial stress. Induction of mitochondrial stress promotes accumulation of GFP-tagged UBL-5 in nuclei of transgenic worms suggesting that UBL-5 effects a nuclear step required for mounting a response to the threat of mitochondrial protein misfolding.

Osman, Hadley C et al. MicroPubl Biol

Lucanic, Mark, Hall, David, Osman, Hadley C, Sedore, Christine A, Foulger, Anna, Jackson, E Grace, Battistoni, Elena T, Lithgow, Gordon J, Guo, Max, Driscoll, Monica, Phillips, Patrick

[MicroPubl Biol, 2021]

The Caenorhabditis Intervention Testing Program (CITP) is a multi-institutional, National Institute on Aging (NIA)-funded consortium with the goal of identifying compounds that will robustly extend lifespan with reproducible effects across genetically diverse Caenorhabditis species and strains (Lucanic et al., 2017). Compounds are prioritized for testing based on computational prediction for lifespan or healthspan effects (Coleman-Hulbert et al., 2019), predicted or known interactions with documented lifespan-regulating pathways, or previous reports for lifespan or healthspan extension in laboratory animals. In this case, diuron was of interest to CITP based on the report of a positive effect on the lifespan of C. elegans strain TJ1060 (spe-9;fer-15) (Lucanic et al., 2018; personal communication). Diuron (1-(3,4-dichlorophenyl)-3,3-dimethylurea) is an herbicide that inhibits photosynthesis by binding photosystem II (Haynes et al., 2000). Diuron has been previously tested in nematode species for toxicity (Neury-Ormanni et al., 2019) and reproductive effects (Mugova et al., 2018), and in both cases showed detrimental effects at high doses only.

Zhao Y et al. (2007) BMC Genomics "Poly-G/poly-C tracts in the genomes of Caenorhabditis."

Zhao Y, O'Neil NJ, Rose AM

[BMC Genomics, 2007]

ABSTRACT: BACKGROUND: In the genome of Caenorhabditis elegans, homopolymeric poly-G/poly-C tracts (G/C tracts) exist at high frequency and are maintained by the activity of the DOG-1 protein. The frequency and distribution of G/C tracts in the genomes of C. elegans and the related nematode, C. briggsae were analyzed to investigate possible biological roles for G/C tracts. RESULTS: In C. elegans, G/C tracts are distributed along every chromosome in a non-random pattern. Most G/C tracts are within introns or are close to genes. Analysis of SAGE data showed that G/C tracts correlate with the levels of regional gene expression in C. elegans. G/C tracts are over-represented and dispersed across all chromosomes in another Caenorhabditis species, C. briggase. However, the positions and distribution of G/C tracts in C. briggsae differ from those in C. elegans. Furthermore, the C. briggsae dog-1 ortholog CBG19723 can rescue the mutator phenotype of C. elegans dog-1 mutants. CONCLUSIONS: The abundance and genomic distribution of G/C tracts in C. elegans, the effect of G/C tracts on regional transcription levels, and the lack of positional conservation of G/C tracts in C. briggsae suggest a role for G/C tracts in chromatin structure but not in the transcriptional regulation of specific genes.

Antika TR et al. (2023) J Biol Chem "Sequence-specific targeting of C. elegans C-Ala to the D-loop of tRNAAla."

Horng JC, Hsu HL, Nazilah KR, Wang CC, Wang TL, Wang SC, Antika TR, Chuang TH, Chrestella DJ, Wang SW, Tseng YK, Pan HC

[J Biol Chem, 2023]

Alanyl-tRNA synthetase (AlaRS) retains a conserved prototype structure throughout its biology. Nevertheless, its C-terminal domain (C-Ala) is highly diverged and has been shown to play a role in either tRNA or DNA binding. Interestingly, we discovered that Caenorhabditis elegans cytoplasmic C-Ala (Ce-C-Ala_c) robustly binds both ligands. How Ce-C-Ala_c targets its cognate tRNA and whether a similar feature is conserved in its mitochondrial counterpart remain elusive. We show that the N- and C-terminal subdomains of Ce-C-Ala_c are responsible for DNA and tRNA binding, respectively. Ce-C-Ala_c specifically recognized the conserved invariant base G¹⁸ in the D-loop of tRNA^Ala through a highly conserved lysine residue, K934. Despite bearing little resemblance to other C-Ala domains, C. elegans mitochondrial C-Ala (Ce-C-Ala_m) robustly bound both tRNA^Ala and DNA and maintained targeting specificity for the D-loop of its cognate tRNA. This study uncovers the underlying mechanism of how C. elegans C-Ala specifically targets the D-loop of tRNA^Ala.

Guven K (1995) Journal of Thermal Biology "Differential expression of hsp70 proteins in response to heat and cadmium in Caenorhabditis elegans."

Guven K

[Journal of Thermal Biology, 1995]

1. The patterns of HSP70 expression induced in Caenorhabditis elegans by mild (31 degrees C) or severe (34 degrees C) heat shock, and by cadmium ions at 31 degrees C, have been compared with those expressed constitutively ill 20 degrees C controls by 1- and a-dimensional immunoblotting. 2. The 2D spot patterns become more complex with increasing severity of stress (34 degrees C > 31 degrees C + Cd > 31 degrees C > 20 degrees C). 3. A stress-inducible transgene construct is minimally active at 31 degrees C, but is abundantly expressed in the presence of cadmium or at 34 degrees C. 4. Differing degrees or types of stress may differentially induce available hsp70

Xu J et al. (2018) J Nanosci Nanotechnol "Carbon Quantum Dots as Fluorescent Probes for Imaging and Detecting Free Radicals in C. elegans."

Wang Q, Guan S, Wang L, Wang M, Zhang Y, Mu Y, Xu J, Wang K, Li J

[J Nanosci Nanotechnol, 2018]

Uniform and hydrophilic carbon quantum dots (C-QDs) were synthesized by calcination and NaOH treatment from an organo-templated zeolite precursor. The color of luminescence was determined by the concentration of C-QDs. These variable-color C-QDs were applied for the first time in the imaging of Caenorhabditis elegans (C. elegans) as a model organism. The effects of C-QDs and possible behavioral changes in C. elegans were evaluated under treatment conditions. We could clearly observe distribution of C-QDs in C. elegans from the fluorescence images. Furthermore, we observed significant and detectable fluorescence quenching of the C-QDs by free radicals in C. elegans. Our work affirms that C-QDs can be developed as imaging probes and as potential fluorescent quantitative probes for detecting free radicals.

Lu L et al. (2021) Mol Immunol "Whole transcriptome analysis of schinifoline treatment in Caenorhabditis elegans infected with Candida albicans."

Shu C, Ma S, Li S, Li Z, Shan C, Chen G, Lu L, Nie W, Wang H

[Mol Immunol, 2021]

Candida albicans is an opportunistic fungal human pathogen that has been causing an increasing number of deaths each year. Due to the widespread use of broad-spectrum antibiotics and immunosuppressants, C. albicans resistance to these therapies has increased. Thus, natural plant inhibitors are being investigated for treating C. albicans infections. Schinifoline is a 4-quinolinone alkaloid with antibacterial, insecticidal, antitumor, and other biological activities. Here, we explored the effects of schinifoline on C. albicans in C. elegans and extracted RNA from uninfected C. elegans, C. elegans infected with C. albicans, and C. elegans infected with C. albicans and treated with 100 mg/l schinifoline. Our results showed that there were significant differences among the three groups. The GO and KEGG pathway analysis suggested that the pathogenicity of C. albicans to C. elegans was caused by abnormal protein function. Schinifoline regulates lysosomal pathway related genes that accelerate the metabolism and degradation of abnormal proteins, thereby inhibiting the negative effects of C. albicans in vivo. These findings advance our understanding of the molecular mechanisms underlying schinifoline inhibition of C. albicans.