Mitochondrial degeneration and dysfunction are a hallmark of aging and aging-related human diseases, including Alzheimer disease, Parkinson disease, Huntington disease, cancer, type 2 diabetes, atherosclerosis, and cardiovascular diseases. Consequently, mitochondria have evolved several surveillance strategies to protect the organelle from damage. At the same time, factors that target mitochondrial proteins and selectively induce apoptosis, for instance of cancer cells, are actively sought after. The mitochondria provide a paradigm to elucidate the network of molecular chaperones and energy-dependent proteases, which function synergistically to maintain protein homeostasis in the mitochondrial matrix. It is widely appreciated that molecular chaperones provide the first line of defense against protein misfolding diseases by promoting folding and preventing aberrant folding and protein aggregation. In addition to their role in protein folding, mitochondrial chaperones, such as Mortalin (mtHsp70) and TRAP1 (mtHsp90) are also widely expressed in most tumor cell types, including colorectal, breast, prostate, and ovarian cancer, which have the highest mortality rates, but strikingly not in highly proliferating, non-tumor cells. Remarkably, down- regulation of TRAP1 abrogates the transforming potential of osteosarcoma, colon carcinoma, and cervix carcinoma cells, supporting a new role of mitochondrial chaperones in the immortalization of cancer cells. Consistently, inhibition of TRAP1 induces apoptosis in prostate cancer cells, underscoring the significance of mitochondrial chaperones as promising new drug targets. The broad and long-term research objective is to provide a molecular understanding of the mitochondrial protein quality control system in vitro and in vivo, to determine the underlying cooperative mechanism and function of the mitochondrial protein folding machinery in normal and pathological states, and how small molecules can be used to modulate mitochondrial chaperone function. The goals of this research will be pursued through the following specific aims: 1) to characterize the mitochondrial protein folding machinery in normal and disease states; 2) to target the structure of TRAP1 with small molecule compounds to modulate its chaperone function; and 3) to determine the structural and molecular basis of TRAP1-substrate interaction. To accomplish our research objective, we will use a multi-pronged in vitro and in vivo approach, which spans different resolution scales and adds to the innovation of the proposed research.

Public Health Relevance

Loss of mitochondrial function is a major contributor to aging and aging-related human diseases, including cancer, type 2 diabetes, neurodegenerative diseases, and metabolic disorders. While molecular chaperones provide the first line of defense against protein misfolding and aggregation, their function (or lack thereof) in pathophysiology remains poorly understood. The broad and long-term research objective is to provide a molecular and mechanistic understanding of the mitochondrial chaperone machinery in physiological processes and pathological states in order that this information can be exploited for the development of new therapeutics.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM111084-04
Application #
9439808
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Wehrle, Janna P
Project Start
2015-03-01
Project End
2019-02-28
Budget Start
2018-03-01
Budget End
2019-02-28
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Baylor College of Medicine
Department
Biochemistry
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Lee, Jungsoon; Sung, Nuri; Yeo, Lythou et al. (2017) Structural determinants for protein unfolding and translocation by the Hsp104 protein disaggregase. Biosci Rep 37:
Chang, Chiung-Wen; Lee, Sukyeong; Tsai, Francis T F (2017) Structural Elements Regulating AAA+ Protein Quality Control Machines. Front Mol Biosci 4:27
Lee, Jungsoon; Sung, Nuri; Mercado, Jonathan M et al. (2017) Overlapping and Specific Functions of the Hsp104 N Domain Define Its Role in Protein Disaggregation. Sci Rep 7:11184
Saliba, Jason; Zabriskie, Ryan; Ghosh, Rajarshi et al. (2016) Pharmacogenetic characterization of naturally occurring germline NT5C1A variants to chemotherapeutic nucleoside analogs. Pharmacogenet Genomics 26:271-9
Sung, Nuri; Lee, Jungsoon; Kim, Ji Hyun et al. (2016) 2.4?Å resolution crystal structure of human TRAP1NM, the Hsp90 paralog in the mitochondrial matrix. Acta Crystallogr D Struct Biol 72:904-11
Sung, Nuri; Lee, Jungsoon; Kim, Ji-Hyun et al. (2016) Mitochondrial Hsp90 is a ligand-activated molecular chaperone coupling ATP binding to dimer closure through a coiled-coil intermediate. Proc Natl Acad Sci U S A 113:2952-7
Jeng, Wilson; Lee, Sukyeong; Sung, Nuri et al. (2015) Molecular chaperones: guardians of the proteome in normal and disease states. F1000Res 4: