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Mitochondrial and lysosomal biogenesis are activated following PINK1/parkin-mediated mitophagy.
J Neurochem. 2016 Jan; 136(2):388-402.JN

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.

Authors+Show Affiliations

Department of Clinical Neuroscience, UCL Institute of Neurology, London, UK.Department of Clinical Neuroscience, UCL Institute of Neurology, London, UK.Department of Clinical Neuroscience, UCL Institute of Neurology, London, UK.Department of Clinical Neuroscience, UCL Institute of Neurology, London, UK.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26509433

Citation

Ivankovic, Davor, et al. "Mitochondrial and Lysosomal Biogenesis Are Activated Following PINK1/parkin-mediated Mitophagy." Journal of Neurochemistry, vol. 136, no. 2, 2016, pp. 388-402.
Ivankovic D, Chau KY, Schapira AH, et al. Mitochondrial and lysosomal biogenesis are activated following PINK1/parkin-mediated mitophagy. J Neurochem. 2016;136(2):388-402.
Ivankovic, D., Chau, K. Y., Schapira, A. H., & Gegg, M. E. (2016). Mitochondrial and lysosomal biogenesis are activated following PINK1/parkin-mediated mitophagy. Journal of Neurochemistry, 136(2), 388-402. https://doi.org/10.1111/jnc.13412
Ivankovic D, et al. Mitochondrial and Lysosomal Biogenesis Are Activated Following PINK1/parkin-mediated Mitophagy. J Neurochem. 2016;136(2):388-402. PubMed PMID: 26509433.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mitochondrial and lysosomal biogenesis are activated following PINK1/parkin-mediated mitophagy. AU - Ivankovic,Davor, AU - Chau,Kai-Yin, AU - Schapira,Anthony H V, AU - Gegg,Matthew E, Y1 - 2015/11/24/ PY - 2015/07/15/received PY - 2015/10/15/revised PY - 2015/10/21/accepted PY - 2015/10/29/entrez PY - 2015/10/29/pubmed PY - 2016/8/2/medline KW - Nrf2 KW - PINK1 KW - Parkinson's disease KW - TFEB KW - lysosomes KW - mitophagy SP - 388 EP - 402 JF - Journal of neurochemistry JO - J. Neurochem. VL - 136 IS - 2 N2 - 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. SN - 1471-4159 UR - https://www.unboundmedicine.com/medline/citation/26509433/Mitochondrial_and_lysosomal_biogenesis_are_activated_following_PINK1/parkin_mediated_mitophagy_ L2 - https://doi.org/10.1111/jnc.13412 DB - PRIME DP - Unbound Medicine ER -