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Mitochondrial and lysosomal biogenesis are activated following <scp>PINK</scp> 1/parkin‐mediated mitophagy
- Source :
- Journal of Neurochemistry
- Publication Year :
- 2015
- Publisher :
- Wiley, 2015.
-
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.
- Subjects :
- 0301 basic medicine
Carbonyl Cyanide m-Chlorophenyl Hydrazone
Time Factors
Ubiquitin-Protein Ligases
Parkinson's disease
Mitochondrial Degradation
Receptors, Cell Surface
PINK1
Biology
Mitochondrion
Transfection
Biochemistry
Nrf2
Parkin
Neuroblastoma
03 medical and health sciences
Cellular and Molecular Neuroscience
Cytosol
lysosomes
Tubulin
Cell Line, Tumor
Mitochondrial Precursor Protein Import Complex Proteins
Sequestosome-1 Protein
Mitophagy
Humans
RNA, Small Interfering
Heat-Shock Proteins
Molecular Basis of Disease
TFEB
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
Autophagy
Membrane Transport Proteins
Mitochondria
Cell biology
Gene Expression Regulation, Neoplastic
030104 developmental biology
Gene Expression Regulation
Mitochondrial biogenesis
Proton Ionophores
Original Article
ORIGINAL ARTICLES
Protein Kinases
Cell Nucleolus
Subjects
Details
- ISSN :
- 14714159 and 00223042
- Volume :
- 136
- Database :
- OpenAIRE
- Journal :
- Journal of Neurochemistry
- Accession number :
- edsair.doi.dedup.....20faae74cb8bbe2008d924d16785203d