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Mitochondrial biogenesis is transcriptionally repressed in lysosomal lipid storage diseases

King Faisal Yambire, Lorena Fernandez-Mosquera, Robert Steinfeld, Christiane Muehle, Elina Ikonen, Ira Milosevic, View ORCID ProfileNuno Raimundo
doi: https://doi.org/10.1101/381376
King Faisal Yambire
1 University Medical Center Goettingen;
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  • For correspondence: ykingfaisal@gmail.com
Lorena Fernandez-Mosquera
1 University Medical Center Goettingen;
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  • For correspondence: l.fernandez.mosquera@gmail.com
Robert Steinfeld
1 University Medical Center Goettingen;
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  • For correspondence: robert.steinfeld@med.uni-goettingen.de
Christiane Muehle
2 Friedrich-Alexander University Erlangen-Nürnberg (FAU);
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  • For correspondence: christiane.muehle@uk-erlangen.de
Elina Ikonen
3 University of Helsinki;
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  • For correspondence: elina.ikonen@helsinki.fi
Ira Milosevic
4 European Neuroscience Institute
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  • For correspondence: i.milosevic@eni-g.de
Nuno Raimundo
1 University Medical Center Goettingen;
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  • ORCID record for Nuno Raimundo
  • For correspondence: nuno.raimundo@med.uni-goettingen.de
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Abstract

Perturbations in mitochondrial function and homeostasis are pervasive in lysosomal storage diseases, but the underlying mechanisms remain unknown. Here, we report a transcriptional program that represses mitochondrial biogenesis and function in lysosomal storage diseases Niemann-Pick type C (NPC) and acid sphingomyelinase deficiency (ASM), in patient cells and mouse tissues. This mechanism is mediated by the transcription factors KLF2 and ETV1, which are both induced in NPC and ASM patient cells. Mitochondrial biogenesis and function defects in these cells are rescued by the silencing of KLF2 or ETV1. Increased ETV1 expression is regulated by KLF2, while the increase of KLF2 protein levels in NPC and ASM stems from impaired signaling downstream sphingosine-1-phosphate receptor 1 (S1PR1), which normally represses KLF2. In patient cells, S1PR1 is undetectable at the plasma membrane and thus unable to repress KLF2. This manuscript provides a mechanistic pathway for the prevalent mitochondrial defects in lysosomal storage diseases.

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Posted February 06, 2019.
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Mitochondrial biogenesis is transcriptionally repressed in lysosomal lipid storage diseases
King Faisal Yambire, Lorena Fernandez-Mosquera, Robert Steinfeld, Christiane Muehle, Elina Ikonen, Ira Milosevic, Nuno Raimundo
bioRxiv 381376; doi: https://doi.org/10.1101/381376
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Mitochondrial biogenesis is transcriptionally repressed in lysosomal lipid storage diseases
King Faisal Yambire, Lorena Fernandez-Mosquera, Robert Steinfeld, Christiane Muehle, Elina Ikonen, Ira Milosevic, Nuno Raimundo
bioRxiv 381376; doi: https://doi.org/10.1101/381376

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