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Mitochondrial and lysosomal biogenesis are activated following PINK1/parkin-mediated mitophagy

Ivankovic, D; Chau, KY; Schapira, AH; Gegg, ME; (2016) Mitochondrial and lysosomal biogenesis are activated following PINK1/parkin-mediated mitophagy. Journal of Neurochemistry , 136 (2) pp. 388-402. 10.1111/jnc.13412. Green open access

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Abstract

Impairment of the autophagy-lysosome pathway (ALP) is implicated with the changes in α-synuclein and mitochondrial dysfunction observed in Parkinson's disease (PD). Damaged mitochondria accumulate PINK1, which then recruits parkin, resultingin ubiquitination of mitochondrial proteins. These can then be bound by the autophagic proteins p62/SQSTM1 and LC3, resulting in degradation of mitochondria by mitophagy. Mutations in PINK1 and parkin genes are a cause of familial PD. We found a significant increase in the expression of p62/SQSTM1 mRNA and protein following mitophagy induction in human neuroblastoma SH-SY5Y cells. p62 protein not only accumulated on mitochondria, but was also greatly increased in the cytosol. Increased p62/SQSMT1 expression was prevented in PINK1 knock down (KD) cells, suggesting increased p62 expression was a consequence of mitophagy induction. The transcription factors Nrf2 and TFEB, which play roles in mitochondrial and lysosomal biogenesis, respectively, can regulate p62/SQSMT1. We report that both Nrf2 and TFEB translocate to the nucleus following mitophagy induction and that the increase in p62 mRNA levels was significantly impaired in cells with Nrf2 or TFEB KD.. TFEB translocation also increased expression of itself and lysosomal proteins such as glucocerebrosidase and cathepsin D following mitophagy induction. We also report that cells with increased TFEB protein have significantly higher PGC-1α mRNA levels, a regulator of mitochondrial biogenesis, resulting in increased mitochondrial content. Our data suggests that TFEB is activated following mitophagy to maintain ALP and mitochondrial biogenesis. Therefore strategies to increase TFEB may improve both the clearance of α-synuclein and mitochondrial dysfunction in PD. This article is protected by copyright. All rights reserved.

Type: Article
Title: Mitochondrial and lysosomal biogenesis are activated following PINK1/parkin-mediated mitophagy
Open access status: An open access version is available from UCL Discovery
DOI: 10.1111/jnc.13412
Publisher version: http://dx.doi.org/10.1111/jnc.13412
Language: English
Additional information: This is the peer reviewed version of the following article: Ivankovic, D; Chau, KY; Schapira, AH; Gegg, ME; (2016) Mitochondrial and lysosomal biogenesis are activated following PINK1/parkin-mediated mitophagy. Journal of Neurochemistry , 136 (2) pp. 388-402, which has been published in final form at http://dx.doi.org/10.1111/jnc.13412. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.
Keywords: Nrf2, PINK1, Parkinson's disease, TFEB, autophagy, glucocerebrosidase, lysosomes, mitophagy, parkin
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Movement Neurosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology
URI: http://discovery.ucl.ac.uk/id/eprint/1472394
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