Mitochondria are ubiquitous and dynamic organelles of eukaryotic organisms critically involved in many cellular processes, including energy production, metabolism, redox control, and programmed cell death. The importance of properly functioning mitochondria to human health is underscored by the findings that mitochondrial dysfunction is responsible for more than 40 human diseases, including cancer, diabetes, obesity, ataxia, and neurodegenerative disorders such as Parkinson's, Alzheimer's, and Huntington's diseases. The long-term goal of this research is to understand, at the molecular level, how mitochondrial function is controlled in normal physiology, and how this process becomes dysregulated in disease states. Although reversible protein phosphorylation is a major mechanism for controlling numerous cellular processes, the role of phosphorylation in regulating mitochondrial function is poorly understood. Mitochondria has been increasingly recognized as centers for receiving, integrating, and transmitting cellular signals, however, very little is presently known about mitochondrial signaling pathways. PTEN- induced putative kinase 1 (PINK1) is a novel mitochondrial protein initially isolated in a screen for potential mediators of the tumor-suppressive activity of PTEN. A connection to cancer is also suggested by the finding that the expression of PINK1 is up-regulated in melanoma and colon carcinoma cells with high metastatic potential. Recently, mutations in the PINK1 gene were identified as a common cause for early- onset, autosomal recessive Parkinson's disease. In Drosophila, loss of PINK1 expression leads to mitochondrial defects and muscle and dopaminergic neuron degeneration. Despite the genetic evidence indicating an essential role of PINK1 in cell survival, how PINK1 regulates mitochondrial function is unknown and the substrates of PINK1 remain to be identified. In this project, the applicant's team will use a combination of biochemical, proteomic, molecular and cell biological approaches to investigate the signaling role of PINK1 in mitochondria, identify PINK1 downstream effectors, and elucidate the molecular mechanisms by which PINK1 protects cells against apoptosis. The results of the proposed studies should advance our knowledge of the fundamental mechanisms governing mitochondrial signaling in all eukaryotic cells, and facilitate the development of effective therapies for treating human mitochondrial diseases.
The importance of properly functioning mitochondria to human health is underscored by the findings that mitochondrial dysfunction is responsible for more than 40 human diseases, including Parkinson's disease, Alzheimer's disease, diabetes, and cancer. The goal of the proposed research is to understand, at the molecular level, how mitochondrial function is controlled in normal physiology and how this process becomes dysregulated in disease states. The results of the proposed studies will provide fundamental information needed for the development of effective therapeutics to treat numerous mitochondrial diseases in human.
|Fallaize, Dana; Chin, Lih-Shen; Li, Lian (2015) Differential submitochondrial localization of PINK1 as a molecular switch for mediating distinct mitochondrial signaling pathways. Cell Signal 27:2543-54|
|Lee, Samuel M; Chin, Lih-Shen; Li, Lian (2012) Therapeutic implications of protein homeostasis in demyelinating peripheral neuropathies. Expert Rev Neurother 12:1041-3|
|Lee, Samuel M; Chin, Lih-Shen; Li, Lian (2012) Protein misfolding and clearance in demyelinating peripheral neuropathies: Therapeutic implications. Commun Integr Biol 5:107-10|
|Lee, Samuel M; Chin, Lih-Shen; Li, Lian (2012) Charcot-Marie-Tooth disease-linked protein SIMPLE functions with the ESCRT machinery in endosomal trafficking. J Cell Biol 199:799-816|
|Lee, Samuel M; Olzmann, James A; Chin, Lih-Shen et al. (2011) Mutations associated with Charcot-Marie-Tooth disease cause SIMPLE protein mislocalization and degradation by the proteasome and aggresome-autophagy pathways. J Cell Sci 124:3319-31|
|Sha, Di; Chin, Lih-Shen; Li, Lian (2010) Phosphorylation of parkin by Parkinson disease-linked kinase PINK1 activates parkin E3 ligase function and NF-kappaB signaling. Hum Mol Genet 19:352-63|
|Chen, Jue; Li, Lian; Chin, Lih-Shen (2010) Parkinson disease protein DJ-1 converts from a zymogen to a protease by carboxyl-terminal cleavage. Hum Mol Genet 19:2395-408|
|Chin, Lih-Shen; Olzmann, James A; Li, Lian (2010) Parkin-mediated ubiquitin signalling in aggresome formation and autophagy. Biochem Soc Trans 38:144-9|
|Giles, Lisa M; Li, Lian; Chin, Lih-Shen (2009) TorsinA protein degradation and autophagy in DYT1 dystonia. Autophagy 5:82-4|
|Pridgeon, Julia W; Webber, Elizabeth A; Sha, Di et al. (2009) Proteomic analysis reveals Hrs ubiquitin-interacting motif-mediated ubiquitin signaling in multiple cellular processes. FEBS J 276:118-31|
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