Role of the mitochondrial matrix processing protease in mitochondrial biogenesis

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DESCRIPTION (provided by applicant): 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.