We have explored the role of mitochondria in Parkinson's disease (PD). At least two gene products mutated in familial PD, PINK1 and Parkin, are now known to mediate autophagic removal of defective mitochondria suggesting that one cause of PD is an impairment of mitochondrial quality control. PINK1 is a kinase located on mitochondria whereas Parkin is an E3 ubiquitin ligase normally located in the cytosol. Upon mitochondrial damage Pink1 recruits cytosolic Parkin to mitochondria to mediate mitophagy revealing a cell biology pathway in mammalian cells where Pink1 works upstream of Parkin. We have found that PINK1 is rapidly turned over in cells. In healthy mitochondria PINK1 is constitutively imported into the inner membrane and degraded by the protease PARL, and maintained at very low levels. When mitochondria sustain damage PINK1 import and degradation is prevented allowing its accumulation on the outer mitochondrial membrane. Thus PINK1 acts as a sensor of mitochondria function. When PINK1 accumulates on the outer mitochondrial membrane of damaged organelles it recruits Parkin to mitochondria from the cytosol. Parkin recruitment requires PINK1 kinase activity but the substrate of PINK1 involved in this process remains unknown. Once on the mitochondria, Parkin ubiquitinates mitochondrial proteins including the GTPases Mfn1 and 2. The loss of ubiqutinated Mfn1 and 2 by proteosomal degradation prevents damaged mitochondria from fusing with healthy mitochondria thereby segregating them fordisposal. The ubiquitin chains Parkin forms on other mitochondrial proteins appear to signal the elimination of mitochondria by autophagy. We found that the proteosome and the AAA ATPase, p97/VCP, Optineurin or NDP52 and ATG5 are required for Parkin mediated mitophagy further indicating the importance of ubiquitin in Parkin mediated mitophagy. Corroborating this model we have found that in cybrid cells that contain a mixture of functional mitochondria with wild type mitochondrial DNA and dysfunctional mitochondria with a mutation in mitochondrial DNA in the COX1 gene, increasing Parkin expression selectively eliminates the damaged mitochondria and enriches for the propagation of wild type mitochondrial DNA. Based on these results we predict that stimulation of the PINK1/Parkin pathway may facilitate mitochondrial quality control and may be of potential therapeutic benefit for patients with mitochondrial diseases and certain forms of Parkinson's disease. An animal model that accumulates mitochondrial DNA mutations corroborates the model that Parkin mediates quality control and rescues neurons of damaged mitochondria. We have begun screening chemical libraries to identify agents that stimulate PINK1 expression and Parkin translocation. We have also completed RNAi screens to identify gene products participating in PINK1 recruitment of Parkin to mitochondria and Parkin stimulation of autophagosome engulfment of mitochondria. These screens led us to identify a strong inflammatory phenotype in both Parkin-/- and PINK1-/- mice following exhaustive exercise (EE) and in Parkin-/-;Mutator mice, which accumulate mitochondrial DNA mutations with age13. Inflammation resulting from both EE and mtDNA mutation is completely rescued by concurrent loss of STING, a central regulator of the type I Interferon response to cytosolic DNA14,15. The loss of DA neurons from the SNc and the motor defect observed in aged Parkin-/-; Mutator mice are also rescued by loss of STING, suggesting that inflammation facilitates this phenotype. Humans with mono- and biallelic Parkin mutations also display elevated cytokines. These results support a role for PINK1- and Parkin-mediated mitophagy in restraining innate immunity and a novel link to PD.
| Sekine, Shiori; Youle, Richard J (2018) PINK1 import regulation; a fine system to convey mitochondrial stress to the cytosol. BMC Biol 16:2 |
| Anding, Allyson L; Wang, Chunxin; Chang, Tsun-Kai et al. (2018) Vps13D Encodes a Ubiquitin-Binding Protein that Is Required for the Regulation of Mitochondrial Size and Clearance. Curr Biol 28:287-295.e6 |
| Sarraf, Shireen A; Youle, Richard J (2018) Parkin mediates mitophagy during beige-to-white fat conversion. Sci Signal 11: |
| Yamano, Koji; Wang, Chunxin; Sarraf, Shireen A et al. (2018) Endosomal Rab cycles regulate Parkin-mediated mitophagy. Elife 7: |
| Pickles, Sarah; Vigié, Pierre; Youle, Richard J (2018) Mitophagy and Quality Control Mechanisms in Mitochondrial Maintenance. Curr Biol 28:R170-R185 |
| Le Guerroué, François; Youle, Richard J (2018) Active state of Parkin. Nat Struct Mol Biol 25:644-646 |
| Stolz, Alexandra; Putyrski, Mateusz; Kutle, Ivana et al. (2017) Fluorescence-based ATG8 sensors monitor localization and function of LC3/GABARAP proteins. EMBO J 36:549-564 |
| Burman, Jonathon L; Pickles, Sarah; Wang, Chunxin et al. (2017) Mitochondrial fission facilitates the selective mitophagy of protein aggregates. J Cell Biol 216:3231-3247 |
| Wang, Chunxin; Youle, Richard (2016) Cell biology: Form follows function for mitochondria. Nature 530:288-9 |
| Richter, Benjamin; Sliter, Danielle A; Herhaus, Lina et al. (2016) Phosphorylation of OPTN by TBK1 enhances its binding to Ub chains and promotes selective autophagy of damaged mitochondria. Proc Natl Acad Sci U S A 113:4039-44 |
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