Biology subjects

Tjahjono, E.

Publications and source records attributed to Tjahjono, E..

7 recordsLinked to original sources

bioRxiv2026

P. aeruginosa liquid-based pathogenesis triggers HLH-30-dependent metabolic rewiring in C. elegans

Innate immunity is the first line of defense against invading pathogens and is essential for maintaining host survival. While the majority of innate immunity studies have focused on pathogen recognition and antimicrobial responses, increasing evidence suggests that lipid metabolism plays a fundamental role in shaping immune function. Understanding how these metabolic pathways contribute to immunity is crucial in the context of bacterial infections caused by opportunistic pathogens such as Pseudomonas aeruginosa. Host defense against P. aeruginosa requires the coordination of innate immune and metabolic responses; however, the mechanisms linking lipid metabolism to pathogen resistance remain poorly understood. Research into the relationship between lipid homeostasis and innate immunity may reveal factors governing host-pathogen interactions and identify novel strategies to enhance resistance to infection. Here, we demonstrate that P. aeruginosa liquid-based pathogenesis (LK-Pa) triggers a shift in host metabolism which differs from the one observed in response to agar-based pathogenesis. Our bioinformatic analyses revealed a highly similar metabolic profile (enrichment of lipid metabolism) in worms exposed to LK-Pa or the iron chelator phenanthroline, suggesting a shared host response to iron deprivation. We further characterized the host genetic factors driving this metabolic shift and established their importance for host defense against LK-Pa as well as liquid-based pathogenesis by Gram-positive pathogens Enterococcus faecalis and Staphylococcus aureus. Notably, our results indicate that LK-Pa triggers host lipid droplet depletion, an upstream component that leads to increased {beta}-oxidation. Finally, we demonstrate that LK-Pa triggers repression of MXL-3 which results in HLH-30-dependent metabolic rewiring.

cell biology↗

bioRxiv2025

Box C/D snoRNPs and MDT-15/MED15 regulate mitochondrial surveillance via fatty acid metabolism

Text AbstractIn response to constant homeostatic threats, organisms have developed complex regulatory networks to monitor cellular functions and restore normal function. Here, we identify MDT-15 and its effectors, the fatty acid desaturases FAT-5, FAT-6, and FAT-7, as activators of the Ethanol and Stress Response (ESRE) mitochondrial surveillance pathway. Our data show that box C/D snoRNPs, which were previously linked to ESRE activation, also regulate FAT-6 and FAT-7 protein levels. Notably, knockdown of mdt-15 or fib-1, a component of box C/D snoRNP complex, increased accumulation of the mitophagic activator PINK-1, the first step in licensing mitophagy, suggesting a relationship between ESRE surveillance and mitophagic activation. Supplementation with downstream unsaturated fatty acid products of FAT-6 and FAT-7 enhanced ESRE and mitophagic activation, but did not affect UPRmt. Since fatty acids activated ESRE and PINK-1 in wild-type and mutant genetic backgrounds, they are likely to act via a mechanism independent of FAT-6 and FAT-7 function. Our results provide insight into a novel interplay between box C/D snoRNPs, MDT-15, and fatty acids in the regulation of mitochondrial surveillance and mitophagy. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=107 SRC="FIGDIR/small/656193v2_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@92f749org.highwire.dtl.DTLVardef@a8f496org.highwire.dtl.DTLVardef@51b28dorg.highwire.dtl.DTLVardef@1a15374_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2025

Cheminformatic identification of small molecules targeting acute myeloid leukemia

Acute myeloid leukemia (AML) is an aggressive hematological malignancy with poor prognosis and high relapse rates when treated with cytotoxic chemotherapeutics. Previously, we identified a family of small molecules that modulate mitochondrial function, referred to as PS127-family compounds. These drugs were selectively toxic to AML and were characterized by two predicted functions: apoptotic agonism and thioredoxin/glutathione reductase inhibition. Here, we uncovered a third critical predicted function, autophagic induction. Using a cheminformatic screen of [~]4.2 million compounds for molecules with high predicted probability for all three functions, we found and validated hits that selectively killed AML cells, activated apoptosis, were dependent upon autophagic activation, and compromised glutathione metabolism by interfering with glutathione reductase, all of which are consistent with predictions. Compound treatment increased pools of cytosolic and mitochondrial ROS, decreased oxygen consumption, and reduced ATP synthesis. Structurally-unrelated compounds caused the same phenotypes, validating our approach of screening for predicted function. Finally, we also observed strong synergy between these compounds and midostaurin and venetoclax, underscoring their therapeutic potential. Key phenotypes, including the compounds impact on glutathione metabolism and synergy with doxorubicin and midostaurin, were confirmed in AML-patient-derived primary cells, validating the potential of these compounds for the development of future AML treatments.

cancer biology↗

bioRxiv2022

Dietary derived Vitamin B12 protects the nematode Caenorhabditis elegans from thiol reducing agents.

We describe a novel SAM methyl transferase in the nematode Caenorhabditis elegans that is upregulated by thiol reducing agents and hydrogen sulfide with expression controlled by the hypoxia inducible factor pathway. This methyl transferase, RIPS-1, is expressed in the gut and hypodermis of this nematode with homologues found in a small subset of eukaryotes and bacteria, many of which can adapt to fluctuations in environmental oxygen levels. We identified RIPS-1 through forward genetic screens as the only gene that when mutated allowed worms to survive normally lethal concentrations of thiol reducing agents such as dithiothreitol (DTT) and {beta}-mercaptoethanol. The RIPS-1 methyl transferase is an important player in the methionine cycle and its activation consumes methionine in a methionine synthetase and vitamin B12-dependant manner. This requirement limits the availability of vitamin B12 in the mitochondrion. Mitochondrial involvement was also established through a targeted enhancer screen that identified methylmalonyl-CoA epimerase as a strong genetic enhancer of RIPS-1 mutant resistance to DTT. Toxicity associated with thiol reducing agent exposure can be overcome in C. elegans by adding methionine, loss of RIPS-1, or by addition of excess vitamin B12. This work highlights the central importance of dietary vitamin B12 in normal metabolic processes in C. elegans and defines a new role in countering reductive stress

biochemistry↗

bioRxiv2022

A Novel Caenorhabditis elegans Gene Network Uncovers Mechanisms of Mitochondrial Maintenance

Mitochondria play key roles in cellular health and metabolism and are a critical determinant of the activation of multiple cell death processes. Although several pathways for regulating and re-establishing mitochondrial homeostasis have been identified within the past twenty years, large gaps remain in our understanding of how cells keep mitochondria healthy. To address this limitation, have developed a network of genes that underlie mitochondrial health. We began by compiling a list of frequently mutated genes using publicly available data from multiple human cancer cell lines. RNAi was used to disrupt orthologous genes in the model organism Caenorhabditis elegans in a series of assays to evaluate these genes ability to support mitochondrial health, as evidenced by precocious activation of mitochondrial autophagy and sensitivity to acute mitochondrial damage. Iterative screening of ~1000 genes yielded a network of 139 genes showing significant connectivity. Functional validation of a panel of genes from the network indicated that disruption of each gene triggered at least one phenotype consistent with mitochondrial dysfunction, including increased fragmentation of the mitochondrial network, abnormal steady-state levels of ATP, NADH, or ROS, and altered oxygen consumption. Importantly, RNAi-mediated knockdown of these genes often exacerbated -synuclein aggregation in a C. elegans model of Parkinsons disease, indicating significant changes to cellular health. Additionally, human orthologs of the final mitochondrial health gene network showed enrichment for roles in a number of human disorders identified in the OMIM database. This gene network provides a foundation for identifying new mechanisms that support mitochondrial and cellular homeostasis.

genetics↗

bioRxiv2021

Small Molecule Stabilization of PINK-1/PINK1 Improves Neurodegenerative Disease

Macroautophagic recycling of dysfunctional mitochondria, known as mitophagy, is essential for mitochondrial homeostasis and cell viability. Accumulation of defective mitochondria and impaired mitophagy have been widely implicated in many neurodegenerative diseases, and loss-of-function mutations of two regulators of mitophagy, PINK1 and Parkin, are amongst the most common causes of recessive Parkinsons disease. Activation of mitophagy via pharmacological treatments may be a feasible approach for combating neurodegeneration. In this effort, we screened [~]45,000 small molecules for the ability to activate mitophagy. A high-throughput, whole-organism, phenotypic screen was conducted by monitoring stabilization of PINK-1/PINK1, a key event in mitophagy activation, in a Caenorhabditis elegans strain carrying a Ppink-1::PINK-1::GFP reporter. We obtained eight hits that induced mitophagy, as evidenced by increased mitochondrial fragmentation and autophagosome formation. Several of the compounds also reduced ATP production, oxygen consumption, mitochondrial mass, and/or mitochondrial membrane potential. Importantly, we found that treatment with two compounds, which we named PS83 and PS106 (more commonly known as sertraline) reduced neurodegenerative disease phenotypes (including delayed paralysis in a C. elegans Alzheimers model) in a PINK-1/PINK1-dependent manner. This report presents a promising step toward the identification of compounds that will stimulate mitochondrial turnover.

cell biology↗

bioRxiv2021

Box C/D Small Nucleolar Ribonucleoproteins Regulate Mitochondrial Surveillance and Innate Immunity

Monitoring of mitochondrial functions is crucial for organismal survival. This task is performed by mitochondrial surveillance or quality control pathways, which are activated by signals originating from mitochondria and relayed to the nucleus (retrograde response) to start the transcription of protective genes. In Caenorhabditis elegans, several systems exist, including the UPRmt, MAPKmt, and the ESRE pathway. These pathways are highly conserved and their loss results in compromised survival following mitochondrial stress. In this study, we found a novel interaction between the box C/D snoRNA core proteins (snoRNPs) and mitochondrial surveillance and innate immunity pathways. We showed that C/D snoRNPs are required for the full expressions of UPRmt and ESRE upon stress. Meanwhile, we found that the loss of C/D snoRNPs increased immune responses. Understanding the "molecular switch" mechanisms of interplay between these pathways may be important for understanding of multifactorial processes, including response to infection or aging.

cell biology↗