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Elife. 2016 Nov 30;5. pii: e20732. doi: 10.7554/eLife.20732.

Loss of Frataxin activates the iron/sphingolipid/PDK1/Mef2 pathway in mammals.

Author information

1
Program in Developmental Biology, Baylor College of Medicine, Houston, United States.
2
Department of Neuroscience, Baylor College of Medicine, Houston, United States.
3
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States.
4
Howard Hughes Medical Institute, Baylor College of Medicine, Houston, United States.
5
Jan and Dan Duncan Neurological Research Institute, Houston, United States.

Abstract

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.

KEYWORDS:

Frataxin; Friedreich's ataxia; Mef2; PDK1; human; iron; mouse; neuroscience; sphingolipid

PMID:
27901468
PMCID:
PMC5130293
DOI:
10.7554/eLife.20732
[Indexed for MEDLINE]
Free PMC Article

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