Defects in mitochondrial function contribute to a wide range of diseases including cancer, cardiovascular disease, and degenerative neural and muscular disorders, including Friedreich's ataxia and Parkinson's, Alzheimer's, and Huntington's diseases. The mitochondrion is important for the production of energy and also plays an important role in other pathways such as intermediary metabolism and signaling. Not only are assembly pathways important for mitochondrial function, but the proteolytic pathways are essential for protein quality control, which impacts biogenesis, morphology, and homeostasis of mitochondria. Friedreich's ataxia can specifically be caused by mutations in frataxin, a subset of which result in defects in maturation. The matrix processing peptidase (MPP) is required for frataxin maturation as well as the maturation and folding of most mitochondrial precursors with an N-terminal targeting sequence, including Pink1 and proteins like fumarase that are dual-localized within the cell. The goal of this study is to characterize novel small molecule modulators for MPP that were identified in a chemical genetic screen.
The aims of this proposal are: (1) Characterize the mechanism by which MPP mediates protein import, which is supported by preliminary data that indicate MPP both cleaves the targeting sequence and has a central role in protein translocation. (2) Determine how inhibiting Pink1 cleavage by MPP arrests translocation at the outer membrane and stimulates Parkin recruitment. Preliminary data supports that the MPP modulators can activate the Pink1/Parkin pathway and may be useful in model systems to selectively induce the pathway. Given the previous success in using small molecule modulators to characterize for protein translocation, exploiting these MPP modulators will provide mechanistic insight into how defects in mitochondrial assembly contribute to neurodegenerative diseases. This study is relevant to public health because it may lead to the development of new strategies to understand and treat degenerative neural diseases such as Friedreich's and Parkinson's diseases.

Public Health Relevance

The mitochondrion generates energy for the cell and is linked to a broad range of diseases, including Friedreich's ataxia and Parkinson's disease. This project will lead to the characterization of small molecule probes that modulate the activity of the matrix processing peptidase, which functions in the processing of mitochondrial targeting sequences, including Pink1 and frataxin. Thus, exploiting these small molecule probes will advance studies in understanding how mitochondrial dysfunction contributes to neurodegeneration.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
1F31GM113648-01
Application #
8838432
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Brown, Patrick
Project Start
2015-07-01
Project End
2018-06-30
Budget Start
2015-07-01
Budget End
2016-06-30
Support Year
1
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095