mTOR hyperactivation in Down Syndrome underlies deficits in autophagy induction, autophagosome formation, and mitophagy
| Autor: | Matteo Bordi, Sandipkumar Darji, Ying Jiang, Ralph A. Nixon, Martin J. Berg, Marian Mellén, Asok Kumar, Yutaka Sato |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Cancer Research Molecular biology Down syndrome Morpholines Ubiquitin-Protein Ligases Immunology PINK1 mTORC1 Mechanistic Target of Rapamycin Complex 2 Mitochondrion Mechanistic Target of Rapamycin Complex 1 mTORC2 Parkin Article 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine Mitophagy Autophagy Humans lcsh:QH573-671 Transcriptomics PI3K/AKT/mTOR pathway Cells Cultured Skin lcsh:Cytology Chemistry TOR Serine-Threonine Kinases Autophagosomes Infant Cell Biology Fibroblasts Cell biology Mitochondria 030104 developmental biology Child Preschool Down Syndrome Lysosomes Protein Kinases 030217 neurology & neurosurgery Signal Transduction |
| Zdroj: | Cell Death & Disease DDFV: Repositorio Institucional de la Universidad Francisco de Vitoria Universidad Francisco de Vitoria DDFV. Repositorio Institucional de la Universidad Francisco de Vitoria instname Cell Death and Disease, Vol 10, Iss 8, Pp 1-17 (2019) |
| ISSN: | 2041-4889 |
| Popis: | Down syndrome (DS), a complex genetic disorder caused by chromosome 21 trisomy, is associated with mitochondrial dysfunction leading to the accumulation of damaged mitochondria. Here we report that mitophagy, a form of selective autophagy activated to clear damaged mitochondria is deficient in primary human fibroblasts derived from individuals with DS leading to accumulation of damaged mitochondria with consequent increases in oxidative stress. We identified two molecular bases for this mitophagy deficiency: PINK1/PARKIN impairment and abnormal suppression of macroautophagy. First, strongly downregulated PARKIN and the mitophagic adaptor protein SQSTM1/p62 delays PINK1 activation to impair mitophagy induction after mitochondrial depolarization by CCCP or antimycin A plus oligomycin. Secondly, mTOR is strongly hyper-activated, which globally suppresses macroautophagy induction and the transcriptional expression of proteins critical for autophagosome formation such as ATG7, ATG3 and FOXO1. Notably, inhibition of mTOR complex 1 (mTORC1) and complex 2 (mTORC2) using AZD8055 (AZD) restores autophagy flux, PARKIN/PINK initiation of mitophagy, and the clearance of damaged mitochondria by mitophagy. These results recommend mTORC1-mTORC2 inhibition as a promising candidate therapeutic strategy for Down Syndrome. post-print 3199 KB |
| Databáze: | OpenAIRE |
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