Mitochondrial Quality Control
Dr. Springer's Translational Cell Biology of Parkinson's Disease Lab has found that loss of function mutations in both PINK1 and PRKN (Parkin) are unequivocally linked to forms of early-onset Parkinson's disease (EOPD). However, reduced expression or inactivation of the encoded enzymes by post-translational modifications also may contribute to late-onset, sporadic Parkinson's disease (PD). Both enzymes orchestrate a cytoprotective response through selective identification, labeling and turnover of worn-out and damaged mitochondria.
This sequential, complex-regulated mitochondrial quality control pathway can be impaired at multiple mechanisms at the level of mitochondria, autophagy and lysosomes. Disrupted mitophagy and the failure to clear damaged mitochondria may result in accumulation and, eventually, cell death. Dopaminergic neurons that selectively degenerate in PD have been described as "living on the edge" and appear to be especially sensitive to impairments of mitophagy. However, given the broad expression patterns of PINK1 and Parkin, mitophagy likely has far-reaching implications for other metabolically active cells and thus several age-related diseases of the brain and beyond. Dr. Springer's team is investigating cell-type specific responses by analyzing different induced pluripotent stem cells (iPSC)-derived cell types and organs from rodent models.
- Hou X, Watzlawik J.O., Fiesel F.C., Springer W. Autophagy in Parkinson's Disease. Journal of Molecular Biology. 2020. doi:10.1016/j.jmb.2020.01.037.
- Truban E, Hou X, Caufield TR, Fiesel FC, Springer W. PINK1, Parkin, and mitrochondrial quality control: What can we learn about Parkinson's disease pathobiology? Journal of Parkinson's Disease. 2017; doi:10.3233/JPD-160989.
- Springer W, Kahle PJ. Regulation of PINK1-Parkin-mediated mitophagy. Autophagy. 2011; doi:10.4161/auto.7.3.14348.
- Geisler S, Holmström KM, Skujat D, Fiesel FC, Rothfuss OC, Kahle PJ, Springer W. PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1. Nature Cell Biology. 2010; doi:10.1038/ncb2012.
- Geisler S, Holmström KM, Treis A, Skujat D, Weber SS, Fiesel FC, Kahle PJ, Springer W. The PINK1/Parkin-mediated mitophagy is compromised by PD-associated mutations. Autophagy. 2010; doi:10.4161/auto.6.7.13286.