Aging is a general physiological deterioration that constitutes the primary risk factor for major human pathologies, including cancer and neurodegenerative diseases. Research to develop cures for these diseases has been hampered because we lack a clear understanding of the factors that underlie the aging contribution. Elucidating these factors remains an important frontier in aging research and will accelerate our ability to intervene in aging-related diseases. Among these factors, loss of protein homeostasis (proteostasis) and the consequent accumulation of aggregated proteins represent a major hallmark of aging. Proteostasis is the guardian of the proteome to ensure proper protein folding, protein-protein interaction, and consequently the organization of the macromolecules and organelles within a cell. Although proteostasis dysfunction during aging has been explored in the context of protein aggregation, a largely unknown consequence of proteostasis dysfunction is the alteration of organelle composition and function. Of relevance to this question, cytosolic protein aggregates formed upon proteostasis defects are anchored on the surface of mitochondria, which allows mitochondria to import these aggregated cytosolic proteins. The goals of this work are to 1) understand how proteostasis defects and aging affect the integrity of mitochondria and other organelles, 2) investigate how proteostasis defects regulate mitochondrial metabolism, and 3) explore mechanisms to rejuvenate the age- related mitochondrial dysfunction and proteostasis defects.
These Aims will be accomplished by using an integration of cutting-edge imaging, proteomics, metabolomics, and biochemical technologies to interrogate related questions in budding yeast, a well-characterized model system for cell biology and aging research. This work will advance our understanding of aging and age-related diseases that are featured with proteostasis defects and mitochondrial dysfunction, while establishing the basis for future explorations in the rejuvenation of aged cells and the interventions for age-related diseases.
Loss of protein homeostasis (proteostasis) and the consequent accumulation of aggregated proteins are hallmarks of aging and many age-related diseases, such as the neurodegenerative diseases. Although proteostasis dysfunction during aging has been explored in the context of protein aggregation, how proteostasis dysfunction affects organelle integrity is still beyond current knowledge. This work will investigate the biological consequences of protein aggregation on the integrity of mitochondria and other organelles during aging, as well as the related rejuvenation mechanisms using budding yeast as a model. The outcomes of this work will significantly improve our understanding of these hallmarks of aging and our ability to intervene in age-related diseases.