TY - JOUR TI - Loss of Frataxin activates the iron/sphingolipid/PDK1/Mef2 pathway in mammals AU - Chen, Kuchuan AU - Ho, Tammy Szu-Yu AU - Lin, Guang AU - Tan, Kai Li AU - Rasband, Matthew N AU - Bellen, Hugo J A2 - Taylor, J Paul VL - 5 PY - 2016 DA - 2016/11/30 SP - e20732 C1 - eLife 2016;5:e20732 DO - 10.7554/eLife.20732 UR - https://doi.org/10.7554/eLife.20732 AB - Friedreich’s ataxia (FRDA) is an autosomal recessive neurodegenerative disease caused by mutations in Frataxin (FXN). Loss of FXN causes 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 of frataxin homolog (fh), a Drosophila homolog of FXN, causes a ROS independent neurodegeneration in flies (Chen et al., 2016). In fh mutants, 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 of Fxn in 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. KW - Frataxin KW - iron KW - sphingolipid KW - PDK1 KW - Mef2 KW - Friedreich's ataxia JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -