Loss of Frataxin induces iron toxicity, sphingolipid synthesis, and Pdk1/Mef2 activation, leading to neurodegeneration

eLife

Manish Jaiswal¹  Matthew N Rasband²  Zhihong Li³  Guang Lin³  Shinya Yamamoto³  Tammy Szu-Yu Ho⁴  Lita Duraine⁵  Nele A Haelterman⁶  Kuchuan Chen⁶  Hugo J Bellen⁶  Tongchao Li⁶  Brett H Graham⁶ 

[1] Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States;Howard Hughes Medical Institute, Baylor College of Medicine, Houston, United States;Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States;Department of Neuroscience, Baylor College of Medicine, Houston, United States;Howard Hughes Medical Institute, Baylor College of Medicine, Houston, United States;Program in Developmental Biology, Baylor College of Medicine, Houston, United States;

关键词: Friedreich's ataxia;    frataxin;    iron;    sphingolipid;    Pdk1;    Mef2;   

DOI  :  10.7554/eLife.16043

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown