Mitochondrial homeostasis in Parkinson's disease

 

 

Tuesday, September 11, 2018 - 4:00pm to 5:00pm
Neurological Institute Auditorium, 1st Fl, 710 West 168th Street, New York
Mitochondrial movement is tightly controlled by the cell to balance energy homeostasis and reduce oxidative stress. The anterograde transport of mitochondria in neurons is mediated by a motor-adaptor complex that includes Miro, milton, and kinesin-1 heavy chain (KHC). Miro is incorporated into the outer mitochondrial membrane (OMM) and anchors mitochondria to microtubules via milton and KHC. Miro situates at a critical nexus to relay multiple cytosolic signals to influence mitochondrial motility. We and others have shown that Miro is removed from the OMM of depolarized mitochondria to the cytosol for proteasome degradation prior to mitophagy, and this Miro removal is primed by PINK1/Parkin-meditated phosphorylation and ubiquitination and LRRK2 interaction. Mutations in LRRK2, PINK1, or Parkin cause familial Parkinson’s disease (PD). We have found a unifying cellular defect in removing Miro from damaged mitochondria in skin fibroblasts or induced pluripotent stem cell (iPSC)-derived neurons, not only from PD patients harboring mutations in LRRK2, PINK1, or Parkin, but also from PD patients with other mutations or no known mutations. Miro is stabilized and remains on damaged mitochondria for longer than normal, prolonging active transport and delaying the onset of mitophagy. This defect renders vulnerable neurons to accumulate damaged mitochondria, causing energy shortage and oxidative stress, and consequently leading to neurodegeneration. We have also found novel factors coming from the inside of the mitochondria that stabilize Miro on the OMM. These factors are sensitized by mitochondrial metabolism and aging in Drosophila. Thus, molecular regulations of Miro may underlie mitochondrial responses to cellular signals and stresses in health and disease.
Name: 
Xinnan Wang, M.D., Ph.D.
Home Institution: 
Stanford University School of Medicine
Event Types: 
Neurobiology Seminars