Zhou J et al. (2018) J Cell Biol "The lysine catabolite saccharopine impairs development by disrupting mitochondrial homeostasis."

Wang F, Zhang F, Qian W, Zhang Q, Wang X, Wang M, Chang Y, Wu S, Zhao L, Gan Q, Ban Z, Guo W, Jing Y, Tang R, Guo Y, Zhou J, Yang C, Wang G

[J Cell Biol, 2018]

Amino acid catabolism is frequently executed in mitochondria; however, it is largely unknown how aberrant amino acid metabolism affects mitochondria. Here we report the requirement for mitochondrial saccharopine degradation in mitochondrial homeostasis and animal development. In <i>Caenorhbditis elegans</i>, mutations in the saccharopine dehydrogenase (SDH) domain of the bi-functional enzyme -aminoadipic semialdehyde synthase AASS-1 greatly elevate the lysine catabolic intermediate saccharopine, which causes mitochondrial damage by disrupting mitochondrial dynamics, leading to reduced adult animal growth. In mice, failure of mitochondrial saccharopine oxidation causes lethal mitochondrial damage in the liver, leading to postnatal developmental retardation and death. Importantly, genetic inactivation of genes that raise the mitochondrial saccharopine precursors lysine and -ketoglutarate strongly suppresses SDH mutation-induced saccharopine accumulation and mitochondrial abnormalities in <i>C. elegans</i> Thus, adequate saccharopine catabolism is essential for mitochondrial homeostasis. Our study provides mechanistic and therapeutic insights for understanding and treating hyperlysinemia II (saccharopinuria), an aminoacidopathy with severe developmental defects.

Zhou J et al. (2022) Nat Cell Biol "A feedback loop engaging propionate catabolism intermediates controls mitochondrial morphology."

Ma T, Duan M, Wang G, Yin Q, Zhou J, Tian F, Yang C, Zhou H, Wang X, Zhang F, Zhang J

[Nat Cell Biol, 2022]

D-2-Hydroxyglutarate (D-2HG) is an -ketoglutarate-derived mitochondrial metabolite that causes D-2-hydroxyglutaric aciduria, a devastating developmental disorder. How D-2HG adversely affects mitochondria is largely unknown. Here, we report that in Caenorhabditis elegans, loss of the D-2HG dehydrogenase DHGD-1 causes D-2HG accumulation and mitochondrial damage. The excess D-2HG leads to a build-up of 3-hydroxypropionate (3-HP), a toxic metabolite in mitochondrial propionate oxidation, by inhibiting the 3-HP dehydrogenase HPHD-1. We demonstrate that 3-HP binds the MICOS subunit MIC60 (encoded by immt-1) and inhibits its membrane-binding and membrane-shaping activities. We further reveal that dietary and gut bacteria affect mitochondrial health by modulating the host production of 3-HP. These findings identify a feedback loop that links the toxic effects of D-2HG and 3-HP on mitochondria, thus providing important mechanistic insights into human diseases related to D-2HG and 3-HP.

Zhou J et al. (2019) J Environ Manage "Effects of bacterial-feeding nematodes on soil microbial activity and the microbial community in oil-contaminated soil."

Yuan Y, Fan H, Chen D, Zhou J, Huang R, Huang G

[J Environ Manage, 2019]

Rapid economic development has caused an increase in serious pollution problems due to the ever-increasing use of oil and its products, thus making oil pollution control an urgent task. Studies have shown that large amounts of bacterial-feeding nematodes are present in oil-contaminated soil; their function is as yet unclear. In this experiment, different densities of Caenorhabditis elegans (C. elegans) were inoculated into artificially simulated oil-contaminated soil to examine their effects on microbial activity and the microbial community in oil-contaminated soil. Six treatments were investigated: sterilized oil-contaminated soil as control 1 (FSP), nematode-free soil as control 2 (S), oil-contaminated soil (SP), oil-contaminated soil+5, 10 or 20 individual C. elegans per gram of dry soil (i.e., SPN5, SPN10, SPN20). Results showed that oil pollution significantly increased the soil basal respiration. However, C. elegans weakened the soil basal respiration to different degrees and soil microbial respiration entropy essentially changed in line with the soil basal respiration. Oil pollution and C. elegans boosted catalase activity in contaminated soil by approximately 64.2-145.1%. Soil urease activity of SPN5, SPN10 and SPN20 was 88.5%, 126.7% and 109.0% stronger, respectively, than that of SP. The inoculation of C. elegans changed the microbial phospholipid fatty acid content in the oil-contaminated soil, including soil bacteria, fungi, actinomycetes, Gram-positive bacteria (G⁺) and Gram-negative bacteria (G^-). Therefore, this research demonstrates that C. elegans can stimulate microbial reproduction in oil-contaminated soil, enhance related soil enzyme activities and regulate soil microbial community structure and diversity, thereby improving the contaminated soil environment and promoting oil degradation.

Zhou J et al. (2018) Environ Sci Pollut Res Int "Effects of bacterial-feeding nematodes and organic matter on microbial activity and oil degradation in contaminated soil."

Cheng S, Tang J, Fan H, Huang R, Zhou J

[Environ Sci Pollut Res Int, 2018]

Increasing rates of oil exploitation and utilization are associated with increasing rates of oil pollution in soil. Nematodes are abundant in soils with or without oil contamination, among which bacterial-feeding nematodes are the dominant group. However, their function in oil-contaminated soil is unclear. This study explores the effects of bacterial-feeding nematode and organic matter addition on microbial activity and oil degradation in contaminated soil. Experiments were conducted using six treatments of oil-contaminated soil: sterilized (Control), nematode-free (OC), nematode addition (OCN), nematode + wheat straw addition (OCNW), nematode + rapeseed cake addition (OCNR), and nematode + biochar addition (OCNB). At the end of a 168-day incubation experiment, the oil concentration of OCN soil was 26.77% lower than that of OC soil, and those of OCNW, OCNR, and OCNB were 12.83%, 27.81%, and 4.77% lower, respectively, than that of OCN soil. Over the experiment, soil microbial biomass carbon, fluorescein diacetate hydrolysis activity, and dehydrogenase activity increased by 4.35-382.30%, 1.75-302.22%, and -2.73-224.55%, respectively, in oil-contaminated soils, with or without nematode and organic matter addition. These results suggest that the addition of organic matter and bacterial-feeding nematodes to oil-contaminated soil can promote the growth and activity of microorganisms that break down oil.

Qian J. Zhou et al. (2008) "Characterization and genomic analysis of H11 gene of Haemonchus contortus"

Hong L. Zhang, Ai F. Du, Qian J. Zhou

[2008]

"H11 was best characterized as &quot;Hidden antigen&quot;, inducing very high levels of antibody-mediated protective immunity, on average a greater than 90% reduction in faecal egg counts (FECs) and &gt;75% reduction in worm burdens. However, recombinant forms of H11, expressed in E. coli and insect cells using recombinant baculovirus, have so far failed to induce protection level similar to that achieved using native antigen. Studies indicate that conformational epitopes and/or glycosylation may be involved in protection.In our study, cDNA of H11 of Haemonchus contortus was cloned and identified via RT-PCR. 2960 bp of cDNA sequence of H11 were amplified from Haemonchus contortus ZJ strain, containing 2919 bp of the integrated open reading frame sharing 99.5% identity with that in database (Smith, 1997). The predicted protein possessed 972 amino acids containing five significant amino acid substitutions of Phe-184 to Leu, Lys-526 to Arg, Glu-561 to Lys, Ser-815 to Phe and Gly-881 to Glu.Due to the probable role of conformational epitopes and glycosylation in protection, a typical region with 347 amino acids from Y224 to E570 was chosen to further study, containing two N-glycosylation sites and one zinc-binding region, corresponding to partial cDNA of H11 from T670 to G1710 expressed in BL21 (DE3).By the alignment analysis between H11 and its homolog in C. elegans and C. briggsae, a partial genomic DNA sequence spanning 4806 bp was amplified using specific primers (HC-GSF and HC-GSR), referring to the patterns of introns and exons of its homologous genes in C. elegans and C. briggsae.Sequence analysis demonstrated typically GT-AG consensus sequences at each intron-exon splice junction and 11 exons were separated by 10 introns in this gemomic DNA sequence, corresponding to 1162 bp cDNA of H11. The 2810 bp 5' flanking region was amplified using the &quot;genome walker&quot; protocol. Except normal transcriptional factors such as TATA box, CCAAT box, more than nine GATA boxes were present in this region, which probably played a certain role in transcription of H11 gene. The antecedent characterizations of H11 may interpret why recombinant antigen failed to induce active protection. "

Zhou S et al. (2011) J Cell Biol "Neural integrity is maintained by dystrophin in C. elegans."

Zhou S, Chen L

[J Cell Biol, 2011]

The dystrophin protein complex (DPC), composed of dystrophin and associated proteins, is essential for maintaining muscle membrane integrity. The link between mutations in dystrophin and the devastating muscle failure of Duchenne's muscular dystrophy (DMD) has been well established. Less well appreciated are the accompanying cognitive impairment and neuropsychiatric disorders also presented in many DMD patients, which suggest a wider role for dystrophin in membrane-cytoskeleton function. This study provides genetic evidence of a novel role for DYS-1/dystrophin in maintaining neural organization in Caenorhabditis elegans. This neuronal function is distinct from the established role of DYS-1/dystrophin in maintaining muscle integrity and regulating locomotion. SAX-7, an L1 cell adhesion molecule (CAM) homologue, and STN-2/-syntrophin also function to maintain neural integrity in C. elegans. This study provides biochemical data that show that SAX-7 associates with DYS-1 in an STN-2/-syntrophin-dependent manner. These results reveal a recruitment of L1CAMs to the DPC to ensure neural integrity is maintained.

Zhou X et al. (2021) J Cell Biol "The HSPG syndecan is a core organizer of cholinergic synapses."

Zhou X, VACHON C, Cizeron M, Romatif O, Bessereau JL, Bulow HE, Jospin M

[J Cell Biol, 2021]

The extracellular matrix has emerged as an active component of chemical synapses regulating synaptic formation, maintenance, and homeostasis. The heparan sulfate proteoglycan (HSPG) syndecans are known to regulate cellular and axonal migration in the brain. They are also enriched at synapses, but their synaptic functions remain more elusive. Here, we show that SDN-1, the sole orthologue of syndecan in C. elegans, is absolutely required for the synaptic clustering of homomeric 7-like acetylcholine receptors (AChRs) and regulates the synaptic content of heteromeric AChRs. SDN-1 is concentrated at neuromuscular junctions (NMJs) by the neurally secreted synaptic organizer Ce-Punctin/MADD-4, which also activates the transmembrane netrin receptor DCC. Those cooperatively recruit the FARP and CASK orthologues that localize 7-like-AChRs at cholinergic NMJs through physical interactions. Therefore, SDN-1 stands at the core of the cholinergic synapse organization by bridging the extracellular synaptic determinants to the intracellular synaptic scaffold that controls the postsynaptic receptor content.

Zhou W et al. (2019) J Lipid Res "A nematode sterol C4-methyltransferase catalyzes a new methylation reaction responsible for sterol diversity."

Fisher PM, Maldonado AJ, Shen Y, Nes WD, Zhou W, Shi H, Leaver DJ, Vanderloop BH

[J Lipid Res, 2019]

Primitive sterol evolution plays an important role in fossil record interpretation and offers potential therapeutic avenues for human disease resulting from nematode infections. Recognition that C4-methyl stenol products (8(14)-lophenol) can be synthesized in bacteria while C4-methyl stanol products (dinosterol) can be synthesized in dinoflagellates and preserved as sterane biomarkers in ancient sedimentary rock is key to eukaryotic sterol evolution. In this regard, nematodes have been proposed to convert dietary cholesterol to 8(14)-lophenol by a secondary metabolism pathway, that could involve sterol C4-methylation analogous to the C2-methylation of hopanoids (radicle-type mechanism), or C24-methylation of sterols (carbocation-type mechanism). Here, we characterized dichotomous cholesterol metabolic pathways in Caenorhabditis elegans that generate 3-oxo sterol intermediates in separate paths to lophanol (4-methyl stanol) and 8(14)-lophenol (4-methyl stenol). We uncovered alternate C3-sterol oxidation and 7-desaturation steps that regulate sterol flux from which branching metabolite networks arise, while lophanol/8(14)-lophenol formation is shown to be dependent on a sterol C4-methyltransferse (4-SMT) that requires 3-oxo sterol substrates and catalyzes a newly discovered 3-keto-enol tautomerism mechanism linked to SAM-dependent methylation. Alignment-specific substrate-binding domains similarly conserved in 4-SMT and 24-SMT enzymes, despite minimal amino acid sequence identity, suggests divergence from a common, primordial ancestor in the evolution of methyl sterols. The combination of these results provides evolutionary leads to sterol diversity and points to cryptic C4-methyl steroidogenic pathways of targeted convergence that mediate lineage-specific adaptations.

Zhou Y et al. (2015) J Lipid Res "Role of CYP eicosanoids in the regulation of pharyngeal pumping and food uptake in Caenorhabditis elegans."

Falck JR, Menzel R, Rothe M, Schunck WH, Zhou Y

[J Lipid Res, 2015]

Cytochrome P450 (CYP)-dependent eicosanoids comprise epoxy- and hydroxy-metabolites of long-chain PUFAs (LC-PUFAs). In mammals, CYP eicosanoids contribute to the regulation of cardiovascular and renal function. Caenorhabditis elegans produces a large set of CYP eicosanoids; however, their role in worm's physiology is widely unknown. Mutant strains deficient in LC-PUFA/eicosanoid biosynthesis displayed reduced pharyngeal pumping frequencies. This impairment was rescued by long-term eicosapentaenoic and/or arachidonic acid supplementation, but not with a nonmetabolizable LC-PUFA analog. Short-term treatment with 17,18-epoxyeicosatetraenoic acid (17,18-EEQ), the most abundant CYP eicosanoid in C. elegans, was as effective as long-term LC-PUFA supplementation in the mutant strains. In contrast, 20-HETE caused decreased pumping frequencies. The opposite effects of 17,18-EEQ and 20-HETE were mirrored by the actions of neurohormones. 17,18-EEQ mimicked the stimulating effect of serotonin when added to starved worms, whereas 20-HETE shared the inhibitory effect of octopamine in the presence of abundant food. In wild-type worms, serotonin increased free 17,18-EEQ levels, whereas octopamine selectively induced the synthesis of hydroxy-metabolites. These results suggest that CYP eicosanoids may serve as second messengers in the regulation of pharyngeal pumping and food uptake in C. elegans.

Zhou K et al. (2009) J Cell Biol "A ZYG-12-dynein interaction at the nuclear envelope defines cytoskeletal architecture in the C. elegans gonad."

Malone CJ, Rolls MM, Hanna-Rose W, Hall DH, Zhou K

[J Cell Biol, 2009]

Changes in cellular microtubule organization often accompany developmental progression. In the Caenorhabditis elegans embryo, the centrosome, which is attached to the nucleus via ZYG-12, organizes the microtubule network. In this study, we investigate ZYG-12 function and microtubule organization before embryo formation in the gonad. Surprisingly, ZYG-12 is dispensable for centrosome attachment in the germline. However, ZYG-12-mediated recruitment of dynein to the nuclear envelope is required to maintain microtubule organization, membrane architecture, and nuclear positioning within the syncytial gonad. We examined gamma-tubulin localization and microtubule regrowth after depolymerization to identify sites of nucleation in germ cells. gamma-Tubulin localizes to the plasma membrane in addition to the centrosome, and regrowth initiates at both sites. Because we do not observe organized microtubules around zyg-12(ct350) mutant nuclei with attached centrosomes, we propose that gonad architecture, including membrane and nuclear positioning, is determined by microtubule nucleation at the plasma membrane combined with tension on the microtubules by dynein anchored at the nucleus by ZYG-12.