Age-related neurodegenerative diseases such as Parkinson's disease (PD) impose tremendous socioeconomic burdens due to the lack of disease-modifying treatment options. Mitochondrial dysfunction is intimately linked to neurodegenerative diseases. How mitochondrial abnormalities arise and how they relate to other features of neurodegenerative diseases such as proteostasis failure, Ca2+ dyshomeostasis, and neuroinflammation are poorly understood. Dynamic control of the structure, function, and distribution of mitochondria is also essential for normal neuronal function, a requirement necessitated by the highly polarized shape and unique physiology of neurons. Despite intensive efforts, many fundamental questions remain regarding the mechanisms linking mitochondrial regulation to neuronal maintenance. Pten-induced kinase 1(PINK1) and Parkin (encoding an E3 ubiquitin ligase), two genes associated with familial PD, have defined a genetic pathway important for mitochondrial and neuronal maintenance in flies and mammals. Identification of this pathway offers a much-needed entry point to understand the regulation of mitochondrial function in response to neuronal activity and metabolic needs, and to decipher the mechanistic link between mitochondrial dysfunction and other pathological hallmarks of disease. Our genetic studies revealed that PINK1/Parkin directs an interconnected mitochondrial quality control (MQC) process important for the maintenance of dopaminergic (DA) neurons. The multifaceted MQC process encompasses translational control of respiratory chain complex (RCC) biogenesis, mitochondrial fission/fusion dynamics, transport, and removal of defective mitochondria by autophagy (mitophagy). In the past funding period we have shown that the conserved target of rapamycin complexes (TORC1 and TORC2) act as important mediators of PINK1-directed MQC. One exciting finding from our investigation is that the PINK1/mTORC2 pathway exerts translational control of nuclear encoded RCC (nRCC) mRNAs. The goal of this proposal is to move away from the status quo of mitophagy-centric focus of PINK1-directed MQC by focusing on the newly discovered translational control function of PINK1/mTORC2 signaling. We will use a unique combination of molecular genetic, genomic, cell biological, and biochemical tools, and move between in vivo fly models and in vitro induced DA neuron (iDN) models. Our central hypothesis is that PINK1/mTORC2 signaling regulates DA neuron function and survival through ribosome-associated co-translational quality control (RQC) of select nuclear-encoded mitochondrial mRNAs, thus mechanistically linking mitochondrial function to protein homeostasis. We propose to elucidate how the RQC pathway mediates the effects of PINK1/mTORC2 on mitochondrial regulation and DA neuron maintenance (Aim 1), and dissect the molecular mechanism of RQC regulation by PINK1/mTORC2 signaling in both Drosophila models and patient-derived iDN models (Aim 2). These studies will significantly advance our understanding of how PINK1/mTORC2 signaling regulates DA neuron homeostasis, shed light on the poorly understood phenomenon of neuronal vulnerability to RQC failure, and potentially lead to novel and rational therapy for PD and other neurological disease conditions.

Public Health Relevance

Mitochondrial dysfunction and protein homeostasis failure are pathological features commonly associated with neurological disorders, but the mechanism behind this association is poorly understood. We have discovered a novel co-translational quality control mechanism that mechanistically links mitochondrial dysfunction and aberrant protein production. By studying the mechanism, function, and regulation of this newly discovered process, this project will generate new knowledge on the pathogenesis of neurodegenerative diseases and help develop novel strategies to treat these devastating brain diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS084412-06
Application #
9764984
Study Section
Neural Oxidative Metabolism and Death Study Section (NOMD)
Program Officer
Gubitz, Amelie
Project Start
2013-12-15
Project End
2024-03-31
Budget Start
2019-04-01
Budget End
2020-03-31
Support Year
6
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Stanford University
Department
Pathology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94304
Wu, Zhihao; Wang, Yan; Lim, Junghyun et al. (2018) Ubiquitination of ABCE1 by NOT4 in Response to Mitochondrial Damage Links Co-translational Quality Control to PINK1-Directed Mitophagy. Cell Metab 28:130-144.e7
Lee, Kyu-Sun; Huh, Sungun; Lee, Seongsoo et al. (2018) Altered ER-mitochondria contact impacts mitochondria calcium homeostasis and contributes to neurodegeneration in vivo in disease models. Proc Natl Acad Sci U S A 115:E8844-E8853
Lee, Seongsoo; Lee, Kyu-Sun; Huh, Sungun et al. (2016) Polo Kinase Phosphorylates Miro to Control ER-Mitochondria Contact Sites and Mitochondrial Ca(2+) Homeostasis in Neural Stem Cell Development. Dev Cell 37:174-189
Chen, Yanbo; Deng, Jianwen; Wang, Peng et al. (2016) PINK1 and Parkin are genetic modifiers for FUS-induced neurodegeneration. Hum Mol Genet 25:5059-5068
Gehrke, Stephan; Wu, Zhihao; Klinkenberg, Michael et al. (2015) PINK1 and Parkin control localized translation of respiratory chain component mRNAs on mitochondria outer membrane. Cell Metab 21:95-108
Lu, Bingwei; Gehrke, Stephan; Wu, Zhihao (2014) RNA metabolism in the pathogenesis of Parkinson?s disease. Brain Res 1584:105-15
Lee, Kyu-Sun; Lu, Bingwei (2014) The myriad roles of Miro in the nervous system: axonal transport of mitochondria and beyond. Front Cell Neurosci 8:330
Lee, Kyu-Sun; Wu, Zhihao; Song, Yan et al. (2013) Roles of PINK1, mTORC2, and mitochondria in preserving brain tumor-forming stem cells in a noncanonical Notch signaling pathway. Genes Dev 27:2642-7