title: Loss of Frataxin activates the iron/sphingolipid/PDK1/Mef2 pathway in mammals.
abstract: Friedreich's ataxia (FRDA) is an autosomal recessive neurodegenerative disease caused by mutations inFrataxin(FXN). Loss ofFXNcauses impaired mitochondrial function and iron homeostasis. An elevated production of reactive oxygen species (ROS) was previously proposed to contribute to the pathogenesis of FRDA. We recently showed that loss offrataxin homolog(fh), aDrosophilahomolog ofFXN, causes a ROS independent neurodegeneration in flies (Chen et al., 2016). Infhmutants, iron accumulation in the nervous system enhances the synthesis of sphingolipids, which in turn activates 3-phosphoinositide dependent protein kinase-1 (Pdk1) and myocyte enhancer factor-2 (Mef2) to trigger neurodegeneration of adult photoreceptors. Here, we show that loss ofFxnin the nervous system in mice also activates an iron/sphingolipid/PDK1/Mef2 pathway, indicating that the mechanism is evolutionarily conserved. Furthermore, sphingolipid levels and PDK1 activity are also increased in hearts of FRDA patients, suggesting that a similar pathway is affected in FRDA.
authors.affiliation: Program in Developmental Biology, Baylor College of Medicine, Houston, United States.
authors.forename: Kuchuan
authors.initials: K
authors.lastname: Chen
authors.affiliation: Department of Neuroscience, Baylor College of Medicine, Houston, United States.
authors.forename: Tammy Szu-Yu
authors.initials: TS
authors.lastname: Ho
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States.
authors.forename: Guang
authors.initials: G
authors.lastname: Lin
authors.affiliation: Program in Developmental Biology, Baylor College of Medicine, Houston, United States.
authors.forename: Kai Li
authors.initials: KL
authors.lastname: Tan
authors.affiliation: Program in Developmental Biology, Baylor College of Medicine, Houston, United States.|Department of Neuroscience, Baylor College of Medicine, Houston, United States.
authors.forename: Matthew N
authors.identifier: 0000-0001-8184-2477
authors.initials: MN
authors.lastname: Rasband
authors.affiliation: Program in Developmental Biology, Baylor College of Medicine, Houston, United States.|Department of Neuroscience, Baylor College of Medicine, Houston, United States.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States.|Howard Hughes Medical Institute, Baylor College of Medicine, Houston, United States.|Jan and Dan Duncan Neurological Research Institute, Houston, United States.
authors.forename: Hugo J
authors.identifier: 0000-0001-5992-5989
authors.initials: HJ
authors.lastname: Bellen
mesh_terms: D000818:Animals; D005621:Friedreich Ataxia / Q000473:pathology; D055786:Gene Knockout Techniques; D006801:Humans; D007501:Iron / Q000378:metabolism*; D033862:Iron-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D064326:MEF2 Transcription Factors / Q000378:metabolism*; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D015398:Signal Transduction; D013107:Sphingolipids / Q000378:metabolism*; D000096923:Frataxin
chemical_list: D007501:Iron; D033862:Iron-Binding Proteins; D064326:MEF2 Transcription Factors; D017346:Protein Serine-Threonine Kinases; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D013107:Sphingolipids; D000096923:Frataxin; C000631429:PDK1 protein, human; C000631433:Pdk1 protein, mouse
keywords: Frataxin; Friedreich's ataxia; Mef2; PDK1; human; iron; mouse; neuroscience; sphingolipid