Miro is a protein on the outer membrane of mitochondria. Miro anchors kinesin motor proteins to mitochondria; the kinesins transport mitochondria to where they need to be. Our recent work demonstrated that two Parkinson’s disease (PD) proteins, PINK1 and Parkin, stop damaged mitochondrial trafficking by degrading Miro, and therefore quarantining damaged mitochondria prior to their degradation via mitophagy. Since Miro is a common target for both PINK1 and Parkin, we propose that Miro plays a critical role in PD pathogenesis.
We hypothesize that in PD the Miro protein is upregulated on damaged mitochondria thus leading to increased mitochondrial motility, delayed mitophagy and resultant neurodegeneration in mutant PD neurons. To test this hypothesis, we will detect Miro protein levels in PD postmortem brain, connective tissue cells of PD patients, and brain cells of PD pre-clinical models. We will also live image damaged mitochondrial motility and mitophagy in nerve fibers of dopaminergic neurons and pre-clinical model neurons in both wildtype and mutant backgrounds.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
The expected results from both the in vitro and in vivo models will elucidate an innovative target, Miro, critical in PD pathogenesis, and provide foundation to empower future clinical research focused on Miro to improve therapeutic intervention.
We expect to see upregulated protein levels of Miro under disease and stressful conditions, and increased mitochondrial motility and delayed mitophagy after mitochondrial damage in PD neurons.
Two Parkinson’s disease (PD)-causing genes, PINK1 and Parkin, degrade the outer mitochondrial membrane protein Miro, which affects mitochondrial transport and clearance called mitophagy. Although impaired mitophagy has been established as a pathogenic mechanism in some PD pre-clinical models, it is unclear whether such cellular abnormalities contribute to the pathogenesis of PD in humans and, importantly, of the more common, sporadic forms of PD. Our data suggest that transport and mitophagy of damaged mitochondria are impaired in postmortem brains, skin fibroblasts, and induced pluripotent stem cell (iPSC)-derived neurons from PD patients. Remarkably, the cases displaying these changes are not only familial but also sporadic. Our study indicates that failure to remove Miro from the mitochondrial surface may constitute a common component of PD pathogenesis, and that therapeutic targeting of Miro may have broad efficacy.
Presentations & Publications
Unstoppable mitochondria in Parkinson's disease. ASCB Minisymposia, 12/2013.
Unstoppable mitochondria in Parkinson's disease. UCSC Bioengineering Department seminar series. 02/2014.
Mitochondrial motility in health and disease. CMCB E5 Mitochondrial Section. 04/2014.
Unstoppable mitochondria in Parkinson's disease. GTC San Francisco. 09/2014.
Chung-Han Hsieh, Alexandre da Cruz, Erica St. Lawrence, Birgit Schuele, Theo Palmer, and Xinnan Wang.(2014). Functional Impairments in Miro Degradation and Mitophagy are a Unifying Feature of Familial and Sporadic Parkinson’s Disease. Under review. Nature.