MDT-15 / Medtronic - LARVOL DELTA

Reduced peroxisomal import triggers peroxisomal retrograde signaling. (PubMed, Cell Rep) - "Specifically, we show that peroxisomal import stress caused by knockdown of the peroxisomal matrix import receptor prx-5/PEX5 triggers NHR-49/peroxisome proliferator activated receptor alpha (PPARα)- and MDT-15/MED15-dependent upregulation of the peroxisomal Lon protease lonp-2/LONP2 and the peroxisomal catalase ctl-2/CAT...While the PRS can be triggered by perturbation of peroxisomal β-oxidation, we also observed hallmarks of PRS activation upon infection with Pseudomonas aeruginosa. We propose that the PRS, in addition to a role in lipid metabolism homeostasis, may act as a surveillance mechanism to protect against pathogens."

Journal • Metabolic Disorders • CAT

Novel Immune Modulators Enhance Caenorhabditis elegans Resistance to Multiple Pathogens. (PubMed, mSphere) - "One of the compounds was mapped to the action of MDT-15/MED15 and NHR-49/HNF4, a pair of transcriptional regulators more generally associated with fatty acid metabolism, potentially highlighting a new link between these biological functions. These studies pave the way for future characterization of the anti-infective activity of the molecules in higher organisms and highlight the compounds' potential utility for further investigation of immune modulation as a novel therapeutic approach."

Journal • Complement-mediated Rare Disorders • Immune Modulation • Immunology • Infectious Disease • Inflammation

A Caenorhabditis elegans ortholog of human selenium-binding protein 1 is a pro-aging factor protecting against selenite toxicity. (PubMed, Redox Biol) - "We identify the transcriptional coregulator MDT-15 and transcription factor EGL-27 as regulators of Y37A1B.5 levels and show that the lifespan extending effect elicited by downregulation of Y37A1B.5 is independent of known MDT-15 interacting factors, such as DAF-16 and NHR-49. In summary, Y37A1B.5 is an ortholog of SELENBP1 that shortens C. elegans lifespan and lowers resistance against oxidative stress, while allowing for a better survival under toxic selenite concentrations."

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Combining Auxin-Induced Degradation and RNAi Screening Identifies Novel Genes Involved in Lipid Bilayer Stress Sensing in Caenorhabditis elegans. (PubMed, G3 (Bethesda)) - "AID-mediated degradation of the mediator MDT-15, a protein required for the upregulation of fatty acid desaturases, induced the activation of lipid bilayer stress-sensitive reporters...Our candidate suppressor genes suggest a network of transcription factors and the integration of multiple tissues for a centralized lipotoxicity response in the intestine. Thus, we demonstrated proof-of-concept for combining AID and RNAi as a new screening strategy and identified eight conserved genes that had not previously been implicated in the lipid bilayer stress response."

Journal • NRF1

Intestinal mir-794 responds to nanopolystyrene by linking insulin and p38 MAPK signaling pathways in nematode Caenorhabditis elegans. (PubMed, Ecotoxicol Environ Saf) - "In the intestine, DAF-16 functioned synergistically with SKN-1 or MDT-15 to regulate the response to nanopolystyrene. Our results suggested that the intestinal mir-794 provided an important epigenetic regulation mechanism to control the response to nanopolystyrene by linking insulin and p38 MAPK signaling pathways in nematodes."

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Citrus aurantium L. var. amara Engl. inhibited lipid accumulation in 3T3-L1 cells and Caenorhabditis elegans and prevented obesity in high-fat diet-fed mice. (PubMed, Pharmacol Res) - "TG content in mdt-15 (XA7702) mutants was not decreased by EA extracts administration, suggesting that EA extracts treatment might inhibit lipid accumulation in C. elegans dependent on mdt-15...No abstract available"

Journal • Preclinical • Genetic Disorders • Obesity

Mitochondrial Dysfunction in C. elegans Activates Mitochondrial Relocalization and Nuclear Hormone Receptor-Dependent Detoxification Genes. (PubMed, Cell Metab) - "Disabling the mdt-15/nhr-45 pathway renders animals more susceptible to a mitochondrial toxin or pathogenic Pseudomonas aeruginosa but paradoxically improves health and extends lifespan in animals with mitochondrial dysfunction caused by a mutation. Thus, some of the health deficits in mitochondrial disorders may be caused by the ineffective activation of detoxification and immune responses, which may be inhibited to improve health."

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Anti-fat effect and mechanism of polysaccharide-enriched extract from Cyclocarya paliurus (Batal.) Iljinskaja in Caenorhabditis elegans. (PubMed, Food Funct) - "In lipid metabolism, CPP down-regulated the expression of the sbp-1 and nhr-49 genes by modulating mdt-15 to prevent the expression of the Δ9-desaturase genes (fat-5, fat-6 and fat-7). Meanwhile, the expression of the acs-2 genes, the downstream of nhr-49, was suppressed by CPP. These findings provided insights into the CPP-induced anti-fat mechanisms, which contributed to the application of CPP in anti-obesity drugs."

Journal • Genetic Disorders • Immunology • Obesity

Lipid metabolic sensors of MDT-15 and SBP-1 regulated the response to simulated microgravity in the intestine of Caenorhabditis elegans. (PubMed, Biochem Biophys Res Commun) - "During the control of response to simulated microgravity, fatty acyl CoA desaturase FAT-6 was identified as the downstream target of intestinal SBP-1. Therefore, the identified signaling cascade of MDT-15-SBP-1-FAT-6 suggested the important function of lipid metabolic sensors in mediating a novel intestinal signaling pathway to regulate the response to simulated microgravity in nematodes."

Journal • Immunology

A Study of the Pharmacokinetics, Safety, and Preliminary Efficacy of MDT-15 in Subjects With Lumbosacral Radiculopathy (clinicaltrials.gov) - P2; N=54; Active, not recruiting; Sponsor: Medtronic Spinal and Biologics; Recruiting ➔ Active, not recruiting

Enrollment closed • Biosimilar

Mediator subunit MDT-15/MED15 and Nuclear Receptor HIZR-1/HNF4 cooperate to regulate toxic metal stress responses in Caenorhabditis elegans. (PubMed, PLoS Genet) - "Lastly, mammalian MDT-15 orthologs bind genomic regulatory regions of metallothionein and zinc transporter genes in a cadmium and zinc-stimulated fashion, and human MED15 is required to induce a metallothionein gene in lung adenocarcinoma cells exposed to cadmium. Collectively, our data show that mdt-15 and hizr-1 cooperate to regulate cadmium detoxification and zinc storage and that this mechanism is at least partially conserved in mammals."

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MDT-15/MED15 permits longevity at low temperature via enhancing lipidostasis and proteostasis. (PubMed, PLoS Biol) - "Thus, lipidostasis regulated by MDT-15 appears to be a limiting factor for proteostasis and longevity at low temperatures. Our findings highlight the crucial roles of lipid regulation in maintaining normal organismal physiology under different environmental conditions."

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Lipid metabolic response to polystyrene particles in nematode Caenorhabditis elegans. (PubMed, Environ Pollut) - "In the intestine, function of MDT-15 and SBP-1 in regulating nanopolystyrene toxicity was under the control of upstream signaling cascade (PMK-1-SKN-1) in p38 MAPK signaling pathway. Therefore, our data raised an important molecular basis for potential protective function of lipid metabolic response in nanopolystyrene exposed nematodes."

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Mechanism of Pentagalloyl Glucose in Alleviating Fat Accumulation in Caenorhabditis elegans. (PubMed, J Agric Food Chem) - "In addition, the expression levels of fat metabolism genes were significantly changed in both conditions by PGG, which include mdt-15, pod-2, elo-2, fat-6, and fat-7 genes modulated fat synthesis; aak-2 and nhr-49 genes participated in fat consumption; and tub-1 gene regulated fat storage. However, fat-5 and acs-2 were downregulated in high-fat worms only, and vit-2 and lipl-4 were downregulated in normal worms only. Our study provided new insights into the role of PGG in alleviating fat accumulation and its underlying mechanism of action in C. elegans."

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Effects of Momordica saponin extract on alleviating fat accumulation in Caenorhabditis elegans. (PubMed, Food Funct) - "Finally, MSE might down-regulate sbp-1 and nhr-49 via mdt-15, and up regulate age-1 via daf-2. And these targets genes together down-regulated the expression of fat-5, fat-6 and fat-7 to decrease fat accumulation. Our results provided new insights into the inhibition of fat accumulation and underlying mechanisms of Momordica saponins in C. elegans, which might be developed into a nutraceutical to ameliorate obesity."

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The receptor tyrosine kinase HIR-1 coordinates HIF-independent responses to hypoxia and extracellular matrix injury. (PubMed, Sci Signal) - "Genetic suppressor screens identified NHR-49 and MDT-15 as transcriptional regulators downstream of HIR-1. Furthermore, hir-1 mutants showed defects in adapting to and recovering from prolonged severe hypoxia. We propose that C. elegans HIR-1 coordinates hypoxia-inducible factor-independent responses to hypoxia and hypoxia-associated ECM remodeling through mechanisms that are likely conserved in other organisms."

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NHR-49/HNF4 integrates regulation of fatty acid metabolism with a protective transcriptional response to oxidative stress and fasting. (PubMed, Aging Cell) - "Similar to its role in lipid metabolism, NHR-49 requires the mediator subunit mdt-15 to promote stress-induced gene expression...However, organic peroxide increases NHR-49 protein levels, by a posttranscriptional mechanism that does not require PMK-1 activation. Together, these findings establish a new role for the HNF4/PPARα-related NHR-49 as a stress-activated regulator of cytoprotective gene expression."

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N-ϒ-(L-Glutamyl)-L-Selenomethionine Inhibits Fat Storage via the Stearoyl-CoA Desaturases FAT-6 and FAT-7 and the Selenoprotein TRXR-1 in Caenorhabditis elegans. (PubMed, Mol Nutr Food Res) - "This study demonstrates that Glu-SeMet inhibits fat accumulation might be associated with FAT-6 and FAT-7 and the selenoprotein TRXR-1 in C. elegans. This study implies a potential for Glu-SeMet as a new treatment for obesity or its complications."

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