Abstract
Impairment of the autophagy–lysosome pathway 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, resulting in 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 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 knockdown. 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 autophagy–lysosome pathway and mitochondrial biogenesis. Therefore, strategies to increase TFEB may improve both the clearance of α‐synuclein and mitochondrial dysfunction in PD. Damaged mitochondria are degraded by the autophagy–lysosome pathway and is termed mitophagy. Following mitophagy induction, the transcription factors Nrf2 and TFEB translocate to the nucleus, inducing the transcription of genes encoding for autophagic proteins such as p62, as well as lysosomal and mitochondrial proteins. We propose that these events maintain autophagic flux, replenish lysosomes and replace mitochondria.
Highlights
Impairment of the autophagy–lysosome pathway is implicated with the changes in a-synuclein and mitochondrial dysfunction observed in Parkinson’s disease (PD)
Expression of p62/SQSTM1 increased following CCCPinduced mitophagy The autophagic protein p62/SQSTM1 is known to co-localise with depolarised mitochondria in order to facilitate their recruitment to AP, which is degraded by macroautophagy
We show that there is a significant increase in the synthesis of the autophagic protein p62 via the transcription factors Nrf2 and transcription factor EB (TFEB) following activation of PINK1/parkin-mediated mitophagy
Summary
Impairment of the autophagy–lysosome pathway is implicated with the changes in a-synuclein and mitochondrial dysfunction observed in Parkinson’s disease (PD). The transcription factors Nrf and TFEB, which play roles in mitochondrial and lysosomal biogenesis, respectively, can regulate p62/SQSMT1 We report that both Nrf and TFEB translocate to the nucleus following mitophagy induction and that the increase in p62 mRNA levels was significantly impaired in cells with Nrf or TFEB knockdown. The failure of macroautophagy and chaperone-mediated autophagy, which control the degradation of damaged mitochondria and asynuclein are considered important in the bioenergetic dysfunction and protein accumulation/aggregation observed in PD (Narendra et al 2008, 2010b; Alvarez-Erviti et al 2010; Dehay et al 2010; Vives-Bauza et al 2010). It has been proposed that K63-linked polyubiquitination of mitochondrial proteins by parkin recruits p62, which polymerises via its PB1 domain, causing the mitochondria to aggregate next to the nucleus prior to recruitment in to AP (Narendra et al 2010a; Okatsu et al 2010)
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