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.
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.
