ArticleeLife2016
Loss of Frataxin induces iron toxicity, sphingolipid synthesis, and Pdk1/Mef2 activation, leading to neurodegeneration.
Article in eLife, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers.
What it found
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Who cites it
46 citing papers in PubMed, 74 citations in OpenAlex.
- Neuropathology of Friedreich ataxia and its links to metabolic pathways.Neurodegenerative disease management · 2026Review
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- Hypomagnetic Fields Influence the Developmental Duration, Fecundity and Temperature Stress Resistance ofBiology · 2026Article
- Ferroptosis in Cancer and Inflammatory Diseases: Mechanisms and Therapeutic Implications.MedComm · 2025Review
- Impacts of mitochondrial dysfunction on axonal microtubule bundles as a potential mechanism of neurodegeneration.Frontiers in neuroscience · 2025Review
- A defect in mitochondrial fatty acid synthesis impairs iron metabolism and causes elevated ceramide levels.Nature metabolism · 2023Article
- What Is the Role of Ferroptosis in Neurodegeneration?Neurology · 2023Article
- SPTSSA variants alter sphingolipid synthesis and cause a complex hereditary spastic paraplegia.Brain : a journal of neurology · 2023Article
- Modulating the Kynurenine pathway or sequestering toxic 3-hydroxykynurenine protects the retina from light-induced damage in Drosophila.PLoS genetics · 2023Article
- A new FRDA mouse model [Frontiers in neuroscience · 2023Article
- The buzz in the field: the interaction between viruses, mosquitoes, and metabolism.Frontiers in cellular and infection microbiology · 2023Review
- Sphingolipids in neurodegenerative diseases.Frontiers in neuroscience · 2023Review
- Skin fibroblast metabolomic profiling reveals that lipid dysfunction predicts the severity of Friedreich's ataxia.Journal of lipid research · 2022Article
- Pharmacological inhibition of sphingolipid synthesis reduces ferroptosis by stimulating the HIF-1 pathway.iScience · 2022Article
- Lipid Dyshomeostasis and Inherited Cerebellar Ataxia.Molecular neurobiology · 2022Review
- Inter-Species Rescue of Mutant Phenotype-The Standard for Genetic Analysis of Human Genetic Disorders inInternational journal of molecular sciences · 2022Review
- In vivo survival and differentiation of Friedreich ataxia iPSC-derived sensory neurons transplanted in the adult dorsal root ganglia.Stem cells translational medicine · 2021Article
- Leigh Syndrome: A Tale of Two Genomes.Frontiers in physiology · 2021Review
- Iron-Sulfur Cluster Complex Assembly in the Mitochondria ofPlants (Basel, Switzerland) · 2020Article
- Hereditary Ataxia: A Focus on Heme Metabolism and Fe-S Cluster Biogenesis.International journal of molecular sciences · 2020Review
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
12 authors at 2 institutions in 1 country.
Funding
Abstract
Mutations in Frataxin (FXN) cause Friedreich's ataxia (FRDA), a recessive neurodegenerative disorder. Previous studies have proposed that loss of FXN causes mitochondrial dysfunction, which triggers elevated reactive oxygen species (ROS) and leads to the demise of neurons. Here we describe a ROS independent mechanism that contributes to neurodegeneration in fly FXN mutants. We show that loss of frataxin homolog (fh) in Drosophila leads to iron toxicity, which in turn induces sphingolipid synthesis and ectopically activates 3-phosphoinositide dependent protein kinase-1 (Pdk1) and myocyte enhancer factor-2 (Mef2). Dampening iron toxicity, inhibiting sphingolipid synthesis by Myriocin, or reducing Pdk1 or Mef2 levels, all effectively suppress neurodegeneration in fh mutants. Moreover, increasing dihydrosphingosine activates Mef2 activity through PDK1 in mammalian neuronal cell line suggesting that the mechanisms are evolutionarily conserved. Our results indicate that an iron/sphingolipid/Pdk1/Mef2 pathway may play a role in FRDA.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.