NPC1-mTORC1 Signaling Couples Cholesterol Sensing to Organelle Homeostasis and Is a Targetable Pathway in Niemann-Pick Type C

Autor: M. Paulina Ordonez, Oliver B. Davis, Roberto Zoncu, Claire F. Maher, Hijai R. Shin, Chun-Yan Lim, Emma Y. Wu, Matthew Kukurugya, Rushika M. Perera
Rok vydání: 2020
Předmět:
Adult
Induced Pluripotent Stem Cells
Cellular homeostasis
mTORC1
Mitochondrion
Biology
Mechanistic Target of Rapamycin Complex 1
Models
Biological

General Biochemistry
Genetics and Molecular Biology

03 medical and health sciences
Mice
0302 clinical medicine
Niemann-Pick C1 Protein
Lysosome
Mitophagy
Organelle
medicine
Animals
Homeostasis
Humans
Molecular Biology
Cells
Cultured

030304 developmental biology
Neurons
Organelles
0303 health sciences
Intracellular Signaling Peptides and Proteins
Niemann-Pick Disease
Type C

Cell Biology
Intracellular Membranes
Cell biology
Mitochondria
medicine.anatomical_structure
Cholesterol
HEK293 Cells
Proteolysis
biological phenomena
cell phenomena
and immunity

NPC1
Cholesterol storage
Lysosomes
030217 neurology & neurosurgery
Developmental Biology
Signal Transduction
Zdroj: Developmental cell. 56(3)
ISSN: 1878-1551
Popis: Lysosomes promote cellular homeostasis through macromolecular hydrolysis within their lumen and metabolic signaling by the mTORC1 kinase on their limiting membranes. Both hydrolytic and signaling functions require precise regulation of lysosomal cholesterol content. In Niemann-Pick type C (NPC), loss of the cholesterol exporter, NPC1, causes cholesterol accumulation within lysosomes, leading to mTORC1 hyperactivation, disrupted mitochondrial function, and neurodegeneration. The compositional and functional alterations in NPC lysosomes and nature of aberrant cholesterol-mTORC1 signaling contribution to organelle pathogenesis are not understood. Through proteomic profiling of NPC lysosomes, we find pronounced proteolytic impairment compounded with hydrolase depletion, enhanced membrane damage, and defective mitophagy. Genetic and pharmacologic mTORC1 inhibition restores lysosomal proteolysis without correcting cholesterol storage, implicating aberrant mTORC1 as a pathogenic driver downstream of cholesterol accumulation. Consistently, mTORC1 inhibition ameliorates mitochondrial dysfunction in a neuronal model of NPC. Thus, cholesterol-mTORC1 signaling controls organelle homeostasis and is a targetable pathway in NPC.
Databáze: OpenAIRE