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 |
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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 |
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