AKT signalling selectively regulates PINK1 mitophagy in SHSY5Y cells and human iPSC-derived neurons

The discovery of mutations within genes associated with autosomal recessive Parkinson’s disease allowed for the identification of PINK1/Parkin regulated mitophagy as an important pathway for the removal of damaged mitochondria. While recent studies suggest that AKT-dependent signalling regulates Par...

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Bibliographic Details
Published in:Scientific reports 2018-06, Vol.8 (1), p.8855-11, Article 8855
Main Authors: Soutar, Marc P. M., Kempthorne, Liam, Miyakawa, Shuichi, Annuario, Emily, Melandri, Daniela, Harley, Jasmine, O’Sullivan, Gregory A., Wray, Selina, Hancock, David C., Cookson, Mark R., Downward, Julian, Carlton, Mark, Plun-Favreau, Hélène
Format: Article
Language:English
Subjects:
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82/29
96/100
Accumulation
AKT protein
Cell Line, Tumor
Humanities and Social Sciences
Humans
Induced Pluripotent Stem Cells
Insulin
Mitochondria
Mitochondria - metabolism
Mitophagy
multidisciplinary
Mutation
Neurons - cytology
Neurons - metabolism
Parkin protein
Parkinson Disease - metabolism
Parkinson's disease
Phosphorylation
Protein Kinases - metabolism
Proto-Oncogene Proteins c-akt - genetics
Proto-Oncogene Proteins c-akt - physiology
PTEN-induced putative kinase
Science
Science (multidisciplinary)
Signal Transduction
Ubiquitin
Ubiquitin - metabolism
Ubiquitin-Protein Ligases - metabolism
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Summary:The discovery of mutations within genes associated with autosomal recessive Parkinson’s disease allowed for the identification of PINK1/Parkin regulated mitophagy as an important pathway for the removal of damaged mitochondria. While recent studies suggest that AKT-dependent signalling regulates Parkin recruitment to depolarised mitochondria, little is known as to whether this can also regulate PINK1 mitochondrial accumulation and downstream mitophagy. Here, we demonstrate that inhibition of AKT signalling decreases endogenous PINK1 accumulation in response to mitochondria depolarisation, subsequent Parkin recruitment, phosphorylation of ubiquitin, and ultimately mitophagy. Conversely, we show that upon stimulation of AKT signalling via insulin, the mitophagy pathway is increased in SHSY5Y cells. These data suggest that AKT signalling is an upstream regulator of PINK1 accumulation on damaged mitochondria. Importantly, we show that the AKT pathway also regulates endogenous PINK1-dependent mitophagy in human iPSC-derived neurons.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-018-26949-6