Targeting Mitochondrial Complex I Disassembly to Reverse Age-Related Cardiac Dysfunction
Description: Aging, a leading risk factor for cardiovascular diseases (CVD) such as heart failure, disrupts mitochondria, causing impaired energy homeostasis and calcium regulation, and increased reactive oxygen species (ROS), all of which contribute to cardiac dysfunction. Mitochondria are the primary source of ROS, playing an important role in redox signaling from the mitochondria to the cell, and conversely, excessive ROS can cause cellular damage. One primary source of ROS is reverse electron transport (RET), driven by particular thermodynamic conditions at complex I. Mitochondrial complex I, comprising ~45 subunits, is essential for ATP production and redox balance. Impaired complex I assembly reduces complex I enzyme activities, causing altered ROS levels and decreased ATP synthesis. Despite the noticeable importance of the RET and complex I structure in mitochondrial health, little is known about whether RET directly drives complex I disassembly, potentially causing disrupted mitochondrial function, particularly in naturally aged hearts. Our preliminary analysis of mitochondrial interactome data, using a quantitative chemical cross-linking with mass spectrometry approach (qXL-MS), demonstrates reduced protein interactions within complex I Q- and N-modules in aged hearts, along with a decrease in complex I-fueled respiration. These results suggest a potential mechanistic link between complex I instability and impaired respiratory capacity in aged hearts. This project tests the hypothesis that RET directly impairs mitochondrial complex I assembly, disrupting mitochondrial function, and that stabilizing complex I via gene therapy can rescue mitochondrial and cardiac function in aged hearts. In Aim 1, I will induce the RET in human-iPSC-derived cardiomyocytes and integrate a qXL-MS with comprehensive mitochondrial bioenergetic tests to measure the link between the RET, complex I disassembly, and mitochondrial function. In Aim 2, I will utilize cardiac-specific NDUFS4 overexpression, a key subunit of complex I, in aged mice via an AAV9 vector, to test whether improved complex I assembly enhances mitochondrial function and cardiac health in aged mice. Results from these aims will have a transformative impact on the cardiac aging field by providing the first insights into the causal role of RET in complex I disassembly and potentially establishing complex I-targeted therapeutic strategies to preserve mitochondrial and cardiac function in aging.
Funder: American Heart Association
Amount: $155,300
Funding type: fellowship
Funder scheme: Postdoctoral Fellowship
Start date: 2026-01-01
End date: 2027-12-31
Investigators: JUNWON HEO, JUNWON HEO
Institution: University of Washington School of Medicine
Subfield: Molecular Biology
Domain: Life Sciences
Funded outputs count: 0
Funder award ID: 26POST1564475
OpenAlex ID: G436332105