ArticleThe Journal of biological chemistry2014
Serine hydrolase inhibitors block necrotic cell death by preventing calcium overload of the mitochondria and permeability transition pore formation.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 28 citations in OpenAlex.
- Mitochondrial dysfunction at the intersection of alcohol use disorder and chronic pain.Function (Oxford, England) · 2026Review
- Prohibitin 1 regulates mtDNA release and downstream inflammatory responses.The EMBO journal · 2022Article
- α/β-Hydrolase Domain (ABHD) Inhibitors as New Potential Therapeutic Options against Lipid-Related Diseases.Journal of medicinal chemistry · 2021Review
- Lipid-metabolizing serine hydrolases in the mammalian central nervous system: endocannabinoids and beyond.Biochimica et biophysica acta. Molecular and cell biology of lipids · 2019Review
- Proteolytic cleavages of MET: the divide-and-conquer strategy of a receptor tyrosine kinase.BMB reports · 2019Review
- Regulation of calcium release from the endoplasmic reticulum by the serine hydrolase ABHD2.Biochemical and biophysical research communications · 2017Article
- CaScientific reports · 2017Article
- Design, synthesis and pharmacological evaluation of new 2-oxo-quinoline derivatives containing α-aminophosphonates as potential antitumor agents.MedChemComm · 2017Article
- Off-target effect of the cPLA2α inhibitor pyrrophenone: Inhibition of calcium release from the endoplasmic reticulum.Biochemical and biophysical research communications · 2016Article
- Alterations in voltage-sensing of the mitochondrial permeability transition pore in ANT1-deficient cells.Scientific reports · 2016Article
- Discovery, Synthesis, and Optimization of Diarylisoxazole-3-carboxamides as Potent Inhibitors of the Mitochondrial Permeability Transition Pore.ChemMedChem · 2015Article
- Necrosis- and apoptosis-related Met cleavages have divergent functional consequences.Cell death & disease · 2015Article
- Study of the role of cytosolic phospholipase A2 alpha in eicosanoid generation and thymocyte maturation in the thymus.PloS one · 2015Article
- CaMKII and stress mix it up in mitochondria.Frontiers in pharmacology · 2014Review
- Deciphering T Cell Immunometabolism with Activity-Based Protein Profiling.Current topics in microbiology and immunologyReview
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Authors and funding
9 authors at 5 institutions in 1 country.
Funding
Abstract
Perturbation of calcium signaling that occurs during cell injury and disease, promotes cell death. In mouse lung fibroblasts A23187 triggered mitochondrial permeability transition pore (MPTP) formation, lactate dehydrogenase (LDH) release, and necrotic cell death that were blocked by cyclosporin A (CsA) and EGTA. LDH release temporally correlated with arachidonic acid release but did not involve cytosolic phospholipase A2α (cPLA2α) or calcium-independent PLA2. Surprisingly, release of arachidonic acid and LDH from cPLA2α-deficient fibroblasts was inhibited by the cPLA2α inhibitor pyrrophenone, and another serine hydrolase inhibitor KT195, by preventing mitochondrial calcium uptake. Inhibitors of calcium/calmodulin-dependent protein kinase II, a mitochondrial Ca(2+) uniporter (MCU) regulator, also prevented MPTP formation and arachidonic acid release induced by A23187 and H2O2. Pyrrophenone blocked MCU-mediated mitochondrial calcium uptake in permeabilized fibroblasts but not in isolated mitochondria. Unlike pyrrophenone, the diacylglycerol analog 1-oleoyl-2-acetyl-sn-glycerol and CsA blocked cell death and arachidonic acid release not by preventing mitochondrial calcium uptake but by inhibiting MPTP formation. In fibroblasts stimulated with thapsigargin, which induces MPTP formation by a direct effect on mitochondria, LDH and arachidonic acid release were blocked by CsA and 1-oleoyl-2-acetyl-sn-glycerol but not by pyrrophenone or EGTA. Therefore serine hydrolase inhibitors prevent necrotic cell death by blocking mitochondrial calcium uptake but not the enzyme releasing fatty acids that occurs by a novel pathway during MPTP formation. This work reveals the potential for development of small molecule cell-permeable serine hydrolase inhibitors that block MCU-mediated mitochondrial calcium overload, MPTP formation, and necrotic cell death.
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