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How PINK1- and Parkin-mediated Mitophagy Prevents Neurodegeneration
PINK1 and Parkin, both mutated in familial PD, normally work intimately together to initiate autophagy of impaired mitochondria. When mitochondria are damaged, Pink1 senses the damage and accumulates specifically on the outer membrane of damaged mitochondria where it phosphorylates ubiquitin chains. These phosphorylated ubiquitin chains on the outer mitochondrial membrane bind to cytosolic Parkin and activate Parkin’s E3 ubiquitin ligase activity yielding a feedback amplification loop that leads to autophagy of individual damaged mitochondria. Downstream of Parkin the machinery that mediates autophagosome recognition of damaged mitochondria links this pathway to genes mutated in ALS. Optineurin and the kinase TBK1, both mutated in familial ALS cases, participate in mitophagy in addition to NDP52. Optineurin and NDP52 bind to ubiquitin chains on mitochondria and also recruit autophagy machinery proteins, including the upstream kinase Ulk1 and the downstream autophagosome marker, LC3, to induce engulfment of the damaged mitochondria. Interestingly, in a murine model of mitochondrial damage, the product of the kinase PINK1 (phospho-S65 ubiquitin) is detected to increase in the cortex, representing a biomarker of PINK1 activity. Although mutations in Parkin and PINK1 in man lead to PD, mice lacking either or both genes have no PD related phenotypes. However, if mice are stressed, either by the exacerbation of mitochondria DNA mutation rates or by exercise, profound inflammatory phenotypes arise, several of which are linked to human PD patients. The inflammation appears to stem from mitochondrial DNA released into the cytosol when mitophagy does not clean up damaged mitochondria. Interestingly, preventing inflammation through the cGAS/STING pathway prevents neurodegeneration in a mouse model and suggests pharmaceutical treatment could potentially mitigate neurodegeneration.