Date of Award

Spring 1-1-2015

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry & Biochemistry

First Advisor

Xuedong Liu

Second Advisor

Amy Palmer

Third Advisor

Natalie Ahn

Fourth Advisor

Hubert Yin

Fifth Advisor

Ding Xue

Abstract

Mutations in PTEN-induced kinase 1 (PINK1) and its downstream E3 ligase Parkin have been linked to recessive familial Parkinson’s disease. The PINK1-Parkin pathway has been shown to regulate mitophagy, anti-apoptosis, mitochondrial dynamics, and mitochondrial mobility.

In my thesis, I identified that PINK1 triggers the activity of Parkin by phosphorylating Parkin at Ser65. Ubiquitin is also phosphorylated by PINK1 at Ser65. The phosphorylated Parkin is activated in an autocatalytic mechanism. Besides Parkin’s role in mitophagy and antiapoptotic pathways, I showed that Parkin could also induce apoptosis by promoting degradation of Mcl-1. The PINK1/Parkin pathway can mediate different cell fate decisions depending on different chemical treatments. I have also successfully developed a chemical genetic tool to probe the activity of PINK1 in mitochondrial functions. Using this tool we revealed that Parkin can be autoactivated in an irreversible manner. We also reported that PINK1 is sensitive to metabolic changes, translation inhibition, and ATP level. Using high-throughput screening techniques, I identified that celastrol, a traditional Chinese medicine, is an inhibitor of the PINK1-Parkin pathway. Celastrol blocks accumulation of the full length PINK1 in the outer mitochondrial membrane upon mitochondrial membrane potential damage and interferes with the interaction between PINK1 and TOM20. Altogether, this thesis work increased our understanding of the molecular mechanisms underlying PINK1-Parkin pathway regulation.

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