The long-term goal of the Xinnan Wang Lab lies at the intersection of mitochondrial cell biology and the mechanisms of neurological disorders, because of the vital importance of mitochondria to neuronal function and neuropathology.
Xinnan Wang's previous research has provided fundamental insights into how different cellular signals regulate mitochondrial motility by controlling a kinesin/adaptor complex distinctively, in response to temporal and spatial needs. The sensitivity of mitochondrial movement to Ca++ is likely to serve as a means by which mitochondria can be recruited to areas of high metabolic demand or low local ATP, and Ca++ achieves this through changes in the conformation of the kinesin/adaptor complex transiently and instantaneously (Wang and Schwarz, Cell, 2009). In contrast, when mitochondria are damaged, components in the kinesin/adaptor complex are subject to proteasomal degradation, which is primed by a Ser/Thr kinase PINK1 and the subsequent action of an E3 ubiquitin ligase Parkin, thereby arresting mitochondria (Wang et al, Cell, 2011). PINK1 and Parkin are two Parkinson’s disease (PD)-associated proteins. It is likely that stopping mitochondria in this manner is an early step in the quarantining of damaged mitochondria for subsequent degradation. In individuals lacking either functional PINK1 or functional Parkin, a failure to isolate and remove the damaged mitochondria will likely contribute to neurodegeneration.
Given the importance of mitochondrial dynamics and function to neuronal health, we set out to ask, in the short-term, how mis-regulated mitochondrial trafficking, clearance and function contribute to Parkinsonian neurodegeneration. For PINK1/Parkin-related PD, an intriguing hypothesis is that damaged mitochondria need to be halted by the PINK1/Parkin pathway in order to undergo degradation through mitophagy. In this manner, the cell can prevent the deleterious effects of malfunctioning mitochondria. This hypothesis raises many key questions. Do damaged mitochondria stop before they undergo mitophagy? Do defective mitochondria accumulate in PINK1/Parkin mutant cells and thereby cause neuronal cell death? Does neurodegeneration arise similarly in other types of PD including both hereditary and idiopathic? The answers to these questions should help achieve deeper understanding of the molecular and cellular functions of PINK1 and Parkin, and the mechanisms underlying the pathogenesis of PD. We are studying these questions by live imaging mitochondria in iPSC (inducible pluripotent stem cells) - derived dopaminergic neurons from PD patients and healthy controls.
The Xinnan Wang Lab is also probing the cellular functions of PINK1 inside healthy mitochondria. Although PINK1’s role on the outer mitochondrial membrane of damaged mitochondria has been extensively studied, PINK1’s role inside healthy mitochondria is largely unknown. We utilize Drosophila genetics, live-imaging, and biochemical as well as cell biological approaches to define PINK1’s functions under physiological conditions. Clarification of the cellular functions of PINK1, a PD-associated Ser/Thr kinase, will provide critical insights into disease pathogenesis.
In the long-term, we will further investigate how mitochondrial dynamics and functions allow neurons to respond to changes in their activity and environments, and how precisely these controls are needed for the health of a neuron. Local signals that regulate mitochondrial transport must be crucial to maintaining energy homeostasis and thereby to supporting neuronal functions. Altered mitochondrial motility may provide an early indicator of neuronal pathology, prior to cell death, either because motility is directly targeted or because it is altered as a consequence of other mitochondrial malfunctions. We look forward to studying those mechanisms and probing their relevance to neurological disorders.