Mitochondrial and lysosomal biogenesis are activated following PINK1/parkin-mediated mitophagy.
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.
Department of Clinical Neuroscience, UCL Institute of Neurology, London, UK.
Davor
D
Ivankovic
Department of Clinical Neuroscience, UCL Institute of Neurology, London, UK.
Kai-Yin
KY
Chau
Department of Clinical Neuroscience, UCL Institute of Neurology, London, UK.
Anthony H V
AH
Schapira
Department of Clinical Neuroscience, UCL Institute of Neurology, London, UK.
Matthew E
ME
Gegg
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000494:pharmacology; D045744:Cell Line, Tumor; D002466:Cell Nucleolus / Q000187:drug effects / Q000378:metabolism; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D063306:Mitophagy / Q000187:drug effects* / Q000235:genetics*; D009447:Neuroblastoma / Q000473:pathology / Q000648:ultrastructure; D011494:Protein Kinases / Q000378:metabolism*; D061209:Proton Ionophores / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000378:metabolism; D000071456:Sequestosome-1 Protein; D013997:Time Factors; D014162:Transfection; D014404:Tubulin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D000099202:PTEN-Induced Putative Kinase
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; D006360:Heat-Shock Proteins; D026901:Membrane Transport Proteins; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D011494:Protein Kinases; D061209:Proton Ionophores; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; D000071456:Sequestosome-1 Protein; D014404:Tubulin; D044767:Ubiquitin-Protein Ligases; D000099202:PTEN-Induced Putative Kinase; C491079:Sqstm1 protein, rat; C064972:TFEB protein, human; C084008:TOMM20 protein, human; C111567:parkin protein
Nrf2; PINK1; Parkinson's disease; TFEB; lysosomes; mitophagy