title: Mitochondrial Quality Control via the PGC1α-TFEB Signaling Pathway Is Compromised by Parkin Q311X Mutation But Independently Restored by Rapamycin.
abstract: Following its activation by PINK1, parkin is recruited to depolarized mitochondria where it ubiquitinates outer mitochondrial membrane proteins, initiating lysosomal-mediated degradation of these organelles. Mutations in the gene encoding parkin, PARK2, result in both familial and sporadic forms of Parkinson's disease (PD) in conjunction with reductions in removal of damaged mitochondria. In contrast to what has been reported for other PARK2 mutations, expression of the Q311X mutation in vivo in mice appears to involve a downstream step in the autophagic pathway at the level of lysosomal function. This coincides with increased PARIS expression and reduced expression of a reciprocal signaling pathway involving the master mitochondrial regulator peroxisome proliferator-activated receptor-gamma coactivator (PGC1α) and the lysosomal regulator transcription factor EB (TFEB). Treatment with rapamycin was found to independently restore PGC1α-TFEB signaling in a manner not requiring parkin activity and to abrogate impairment of mitochondrial quality control and neurodegenerative features associated with this in vivo model. Losses in PGC1α-TFEB signaling in cultured rat DAergic cells expressing the Q311X mutation associated with reduced mitochondrial function and cell viability were found to be PARIS-dependent and to be independently restored by rapamycin in a manner requiring TFEB. Studies in human iPSC-derived neurons demonstrate that TFEB induction can restore mitochondrial function and cell viability in a mitochondrially compromised human cell model. Based on these data, we propose that the parkin Q311X mutation impacts on mitochondrial quality control via PARIS-mediated regulation of PGC1α-TFEB signaling and that this can be independently restored via upregulation of TFEB function.
  
  
  CONCLUSIONS
  Mutations in PARK2 are generally associated with loss in ability to interact with PINK1, impacting on autophagic initiation. Our data suggest that, in the case of at least one parkin mutation, Q311X, detrimental effects are due to inhibition at the level of downstream lysosomal function. Mechanistically, this involves elevations in PARIS protein levels and subsequent effects on PGC1α-TFEB signaling that normally regulates mitochondrial quality control. Treatment with rapamycin independently restores PGC1α-TFEB signaling in a manner not requiring parkin activity and abrogates subsequent mitochondrial impairment and neuronal cell loss. Taken in total, our data suggest that the parkin Q311X mutation impacts on mitochondrial quality control via PARIS-mediated regulation of PGC1α-TFEB signaling and that this can be independently restored via rapamycin.
authors.affiliation: Buck Institute for Research on Aging, Novato, California 94945.
authors.forename: Almas
authors.initials: A
authors.lastname: Siddiqui
authors.affiliation: Buck Institute for Research on Aging, Novato, California 94945.
authors.forename: Dipa
authors.initials: D
authors.lastname: Bhaumik
authors.affiliation: Buck Institute for Research on Aging, Novato, California 94945.
authors.forename: Shankar J
authors.initials: SJ
authors.lastname: Chinta
authors.affiliation: Buck Institute for Research on Aging, Novato, California 94945.
authors.forename: Anand
authors.initials: A
authors.lastname: Rane
authors.affiliation: Buck Institute for Research on Aging, Novato, California 94945.
authors.forename: Subramanian
authors.initials: S
authors.lastname: Rajagopalan
authors.affiliation: Buck Institute for Research on Aging, Novato, California 94945.
authors.forename: Christopher A
authors.identifier: http://orcid.org/0000-0001-9621-860X
authors.initials: CA
authors.lastname: Lieu
authors.affiliation: Buck Institute for Research on Aging, Novato, California 94945.
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: Lithgow
authors.affiliation: Buck Institute for Research on Aging, Novato, California 94945 jandersen@buckinstitute.org.
authors.forename: Julie K
authors.identifier: http://orcid.org/0000-0003-1324-4875
authors.initials: JK
authors.lastname: Andersen
mesh_terms: D000818:Animals; D001343:Autophagy; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000502:physiology*; D003433:Crosses, Genetic; D059290:Dopaminergic Neurons / Q000166:cytology; D042967:Electron Transport Complex I / Q000502:physiology; D005106:Exploratory Behavior; D006801:Humans; D008247:Lysosomes / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D008928:Mitochondria / Q000502:physiology*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D017354:Point Mutation; D051381:Rats; D012097:Repressor Proteins / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D020123:Sirolimus / Q000494:pharmacology*; D014157:Transcription Factors / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D012097:Repressor Proteins; C484068:Tcfeb protein, mouse; D014157:Transcription Factors; C557561:ZNF746 protein, mouse; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D042967:Electron Transport Complex I; D020123:Sirolimus
keywords: PGC1α; Parkinson's; TFEB; autophagy; mitochondria; parkin