RT Journal Article
SR Electronic
T1 Mitochondrial biogenesis is transcriptionally repressed in lysosomal lipid storage diseases
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 381376
DO 10.1101/381376
A1 King Faisal Yambire
A1 Lorena Fernandez-Mosquera
A1 Robert Steinfeld
A1 Christiane Muehle
A1 Elina Ikonen
A1 Ira Milosevic
A1 Nuno Raimundo
YR 2019
UL http://biorxiv.org/content/early/2019/02/06/381376.abstract
AB 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.