Thursday, May 22, 2025
5/22/2025
Mitochondrial Fidelity and Homeostasis - PROJECT SUMMARY/ABSTRACT Mitochondria are complex, dynamic organelles that are essential in virtually all eukaryotes. They play important roles in various vital processes including energy conversion, synthesis of iron-containing cofactors and metabolic intermediates, immune signaling, and cell fate choices. Although knowledge about mitochondrial biology is increasing, the mechanistic understanding of how mitochondrial functions are established, maintained, and adjusted in response to physiological and stress cues remains incomplete. This is significant as said mechanisms are highly relevant to both normal cellular physiology and a wide range of Mendelian and common age-related human disorders – including glaucoma, hearing loss, Parkinsonism, amyotrophic lateral sclerosis, various neuropathies, dementia, and certain cancers – for which no effective therapies currently exist. The overarching goal of this research program is to determine how evolutionary conserved mitochondrial quality control modules function to maintain cell survival and how these functions can be manipulated to achieve clinical benefits. Unified by the topic of mitochondrial fidelity and protein homeostasis, the program utilizes multidisciplinary approaches to address key gaps in knowledge about conserved mechanisms through which compartmentalized protein folding, stability, assembly, and membrane integrity are safeguarded to ensure proper mitochondrial functions. The proposed studies focus on the following directions: 1) Understanding disease-relevant mechanisms that govern proteolytic and proteostatic control at the inner mitochondrial membrane; and 2) Elucidating how a delicate protein homeostasis in the mitochondrial matrix is established and maintained. In each direction, the proposed work will focus on a group of dedicated factors that mediate protein, ion, and metabolic homeostasis in mitochondrial subcompartments, thereby ensuring the organelle's self-preservation under basal and stress conditions. Capitalizing on previous findings and novel tools and approaches developed by the PI and colleagues, the team will identify and characterize the mechanisms behind these processes. Expected outcomes will deepen the fundamental understanding of mitochondrial biology and related pathogenic mechanisms of human diseases stemming from progressive mitochondrial dysfunction due to quality control of failing organelles.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).