ArticlePLoS pathogens2020
Sterol 14-α-demethylase is vital for mitochondrial functions and stress tolerance in Leishmania major.
Article in PLoS pathogens, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 34 citations in OpenAlex.
- Limonene and carvacrol combined with drugs that inhibit ergosterol synthesis are potent against Leishmania major.Naunyn-Schmiedeberg's archives of pharmacology · 2026Article
- Sterol Endoperoxides and Their Antileishmanial Effects: Influence on Viability, Oxygen Metabolism and Sterol Synthesis.Molecules (Basel, Switzerland) · 2026Article
- Functional Dissection ofToxins · 2026Article
- C14DM Ablation Leads to Reduced Tolerance to Plasma Membrane Stress and Increased Drug Sensitivity inInternational journal of molecular sciences · 2025Article
- Unravelling drug resistance in leishmaniasis: genomic adaptations and emerging therapies.Frontiers in molecular biosciences · 2025Review
- CYP5122A1 encodes an essential sterol C4-methyl oxidase in Leishmania donovani and determines the antileishmanial activity of antifungal azoles.Nature communications · 2024Article
- Molecular Characterization of Sterol C4-Methyl Oxidase inInternational journal of molecular sciences · 2024Article
- Evaluation of theACS infectious diseases · 2024Article
- Article
- Ethanolaminephosphate cytidylyltransferase is essential for survival, lipid homeostasis and stress tolerance in Leishmania major.PLoS pathogens · 2023Article
- Ethanolaminephosphate cytidyltransferase is essential for survival, lipid homeostasis and stress tolerance inbioRxiv : the preprint server for biology · 2023Article
- Amphotericin B resistance in Leishmania mexicana: Alterations to sterol metabolism and oxidative stress response.PLoS neglected tropical diseases · 2022Article
- The Natural Alkaloid Tryptanthrin Induces Apoptosis-like Death inTropical medicine and infectious disease · 2022Article
- In-Depth Quantitative Proteomics Characterization of In Vitro Selected Miltefosine Resistance inProteomes · 2022Article
- Repurposing Lansoprazole and Posaconazole to treat leishmaniasis: Integration of in vitro testing, pharmacological corroboration, and mechanisms of action.Journal of food and drug analysis · 2022Article
- Endogenous Sterol Synthesis Is Dispensable forFrontiers in microbiology · 2022Article
- Balancing de novo synthesis and salvage of lipids by Leishmania amastigotes.Current opinion in microbiology · 2021Review
- Unexpected Role of Sterol Synthesis in RNA Stability and Translation inBiomedicines · 2021Article
- In Silico Insights into the Mechanism of Action of Epoxy-α-Lapachone and Epoxymethyl-Lawsone inMolecules (Basel, Switzerland) · 2021Article
- Electron donor cytochrome b5 is required for hyphal tip accumulation of sterol-rich plasma membrane domains and membrane fluidity inApplied and environmental microbiology · 2021Article
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Sterol 14-α-demethylase (C14DM) is a key enzyme in the biosynthesis of sterols and the primary target of azoles. In Leishmania major, genetic or chemical inactivation of C14DM leads to accumulation of 14-methylated sterol intermediates and profound plasma membrane abnormalities including increased fluidity and failure to maintain ordered membrane microdomains. These defects likely contribute to the hypersensitivity to heat and severely reduced virulence displayed by the C14DM-null mutants (c14dm‾). In addition to plasma membrane, sterols are present in intracellular organelles. In this study, we investigated the impact of C14DM ablation on mitochondria. Our results demonstrate that c14dm‾ mutants have significantly higher mitochondrial membrane potential than wild type parasites. Such high potential leads to the buildup of reactive oxygen species in the mitochondria, especially under nutrient-limiting conditions. Consistent with these mitochondrial alterations, c14dm‾ mutants show impairment in respiration and are heavily dependent on glucose uptake and glycolysis to generate energy. Consequently, these mutants are extremely sensitive to glucose deprivation and such vulnerability can be rescued through the supplementation of glucose or glycerol. In addition, the accumulation of oxidants may also contribute to the heat sensitivity exhibited by c14dm‾. Finally, genetic or chemical ablation of C14DM causes increased susceptibility to pentamidine, an antimicrobial agent with activity against trypanosomatids. In summary, our investigation reveals that alteration of sterol synthesis can negatively affect multiple cellular processes in Leishmania parasites and make them vulnerable to clinically relevant stress conditions.
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