| Autor: |
Tetsushi Kataura, Lucia Sedlackova, Congxin Sun, Gamze Kocak, Niall Wilson, Peter Banks, Faisal Hayat, Sergey Trushin, Eugenia Trushina, Oliver D. K. Maddocks, John E. Oblong, Satomi Miwa, Masaya Imoto, Shinji Saiki, Daniel Erskine, Marie E. Migaud, Sovan Sarkar, Viktor I. Korolchuk |
| Jazyk: |
angličtina |
| Rok vydání: |
2024 |
| Předmět: |
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| Zdroj: |
Cell Death and Disease, Vol 15, Iss 5, Pp 1-13 (2024) |
| Druh dokumentu: |
article |
| ISSN: |
2041-4889 |
| DOI: |
10.1038/s41419-024-06770-y |
| Popis: |
Abstract Impairment of autophagy leads to an accumulation of misfolded proteins and damaged organelles and has been implicated in plethora of human diseases. Loss of autophagy in actively respiring cells has also been shown to trigger metabolic collapse mediated by the depletion of nicotinamide adenine dinucleotide (NAD) pools, resulting in cell death. Here we found that the deficit in the autophagy-NAD axis underpins the loss of viability in cell models of a neurodegenerative lysosomal storage disorder, Niemann-Pick type C1 (NPC1) disease. Defective autophagic flux in NPC1 cells resulted in mitochondrial dysfunction due to impairment of mitophagy, leading to the depletion of both the reduced and oxidised forms of NAD as identified via metabolic profiling. Consequently, exhaustion of the NAD pools triggered mitochondrial depolarisation and apoptotic cell death. Our chemical screening identified two FDA-approved drugs, celecoxib and memantine, as autophagy activators which effectively restored autophagic flux, NAD levels, and cell viability of NPC1 cells. Of biomedical relevance, either pharmacological rescue of the autophagy deficiency or NAD precursor supplementation restored NAD levels and improved the viability of NPC1 patient fibroblasts and induced pluripotent stem cell (iPSC)-derived cortical neurons. Together, our findings identify the autophagy-NAD axis as a mechanism of cell death and a target for therapeutic interventions in NPC1 disease, with a potential relevance to other neurodegenerative disorders. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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Full text from SpringerLink