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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.<\/jats:p>","DOI":"10.7554\/elife.16043","type":"journal-article","created":{"date-parts":[[2016,6,25]],"date-time":"2016-06-25T07:59:57Z","timestamp":1466841597000},"source":"Crossref","is-referenced-by-count":78,"title":["Loss of Frataxin induces iron toxicity, sphingolipid synthesis, and Pdk1\/Mef2 activation, leading to neurodegeneration"],"prefix":"10.7554","volume":"5","author":[{"given":"Kuchuan","family":"Chen","sequence":"first","affiliation":[{"name":"Program in Developmental Biology, Baylor College of Medicine, Houston, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guang","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nele 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