Heart disease is the leading cause of death of both men and women in the US with more than 900,000 deaths each year. Heart failure is a complex disorder, characterized by impaired myocardium contractile ability that delivers inadequate amounts of blood to meet demands of all organs. In the heart, mitochondrial oxidative phosphorylation is the source of 90% of the myocardial energy requirement. In the progression of heart failure, mitochondrial dysfunction has become widely accepted as a key part of maladaptive remodeling. Changes in mitochondrial function during heart failure have remained difficult to define on a molecular level and include altered protein levels, conformations and protein-protein interactions. Elevation in NADH/NAD+ ratio caused by cardiac overload was previously found to regulate mitochondrial protein lysine acetylation and result in changes in protein interactions involving a primary regulator of mitochondrial permeability transition pore sensitization to stress. Large-scale quantitative interactome analysis could reveal what protein conformational and interaction changes are involved in heart failure and provide new targets that can be tested for alleviation in cardiac hypertrophy and dysfunction in heart failure models. This project will develop isobaric quantitative Protein Interaction Reporter (iqPIR) technologies and apply them to study mitochondrial protein interactions and conformational regulation in heart failure. In addition, parallel reaction monitoring assays will be developed for iqPIR cross-linked peptides to yield a generally useful method for quantification of protein interactions and conformational features in any future mitochondrial study.

Public Health Relevance

Heart disease is the leading cause of death of both men and women in the US with more than 900,000 deaths each year. In the heart, mitochondrial oxidative phosphorylation is the source of 90% of the myocardial energy requirement and mitochondrial dysfunction has become widely accepted as a key part of maladaptive remodeling during progressive heart failure. This project will develop and apply advanced technologies to quantify mitochondrial protein interactions and conformational regulation in heart failure to reveal critical changes that mediate mitochondrial dysfunction.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL144778-02
Application #
9944320
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Luo, James
Project Start
2019-07-01
Project End
2023-06-30
Budget Start
2020-07-01
Budget End
2021-06-30
Support Year
2
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Washington
Department
Genetics
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195