Saturday, December 21, 2024
12/21/2024
PROJECT SUMMARY Cardiovascular complications account for the majority of deaths in diabetic patients. Mitochondrial dysfunction is central to the disease and it precipitates contractile impairment, leading to death. However, the precise mechanisms that cause mitochondrial dysfunction in the diabetic heart remain unclear. Using type 2 diabetic human (patient) and mouse (db/db) models, we observed pronounced disruption to mitochondrial structure and function, which were associated with the loss of mitochondrial proteins. The vast majority of mitochondrial proteins are nuclear genome-encoded and require import into the mitochondrion. Import occurs through a coordinated set of machinery containing an active motor, driven by mitochondrial heat shock protein 70 (mtHsp70). We observed decreased mtHsp70 content in cardiac mitochondria from type 2 diabetic patients and db/db mice, and a decrease in mitochondrial protein import. Following import, mitochondrial proteins are refolded into native structures to become functional. MtHsp70 also participates in the refolding process, and works synergistically with Lon Peptidase 1, Mitochondrial (LonP1), an AAA+ protease of the mitochondrial matrix. We have also observed a decrease in LonP1 in the type 2 diabetic heart. When mitochondrial protein import is not functioning properly, aggregated nuclear genome-encoded proteins accumulate on the exterior of the mitochondrion leading to a phenomenon termed mitochondrial precursor over-accumulation stress. Currently, it is unclear what factors contribute to a decrease in protein import efficiency and refolding or whether manipulation of these processes can restore mitochondrial proteomic make-up, mitochondrial function and cardiac contractile performance in the diabetic heart. Our proposed studies address this critical gap in knowledge. The information will enhance our understanding of these processes and aid in the development of therapeutic strategies that target specific import constituents that contribute to loss of mitochondrial proteins. The central hypothesis to be tested is that decreased protein import and refolding in the type 2 diabetic heart causes loss of mitochondrial proteins and mitochondrial precursor over-accumulation stress leading to mitochondrial dysfunction and contractile impairment. The objectives of this application are to (1) identify submitochondrial locations where protein import is compromised in type 2 diabetic mitochondria and the impact on import machinery; (2) evaluate the impact of type 2 diabetes mellitus on mitochondrial protein refolding and the synergistic influence of mtHsp70 and LonP1; and (3) determine the extent of mitochondrial and proteomic stress that occurs in the type 2 diabetic heart, due to failed mitochondrial protein import contributing to mitochondrial precursor over-accumulation stress. Completion of these studies is expected to provide fundamental molecular insight into the mechanisms contributing to the loss of nuclear genome-encoded mitochondrial proteins in the type 2 diabetic heart and the cellular consequences leading to mitochondrial and cardiac dysfunction.
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