Understanding cardiac metabolism through elucidation of mitochondrial protein-protein interactions

Abstract

Cardiovascular disease is the leading cause of death worldwide, yet developments of new treatment has been stalled for nearly three decades and novel concepts and strategies are urgently needed. Mitochondria play a central role in cardiac physiology due to the extraordinary energy demands of the heart. It is well recognized that mitochondrial and metabolic remodeling can be maladaptive in the cardiac response to acute and chronic stress, therefore, treatments that specifically target mitochondrial metabolism would be highly desirable. Our limited understanding of mechanisms that connect mitochondrial dysfunction to cellular responses to stress has hindered progress of therapeutic innovation. In order to gain a more comprehensive understanding of the mitochondrial compartment, we used cross-linking mass spectrometry to determine the protein interaction landscape in respiring isolated mitochondria, intact cardiac tissue, and from animal models of heart failure. These efforts uncovered structural insight into how proteins behave in their native environments and in the presence of pathological stress. Comprehensive visualization of the diverse mitochondrial protein landscape is expected to pave for new therapies and novel drug candidates for heart failure. Furthermore, advancement of a technological strategy for system-wide study of proteins is applicable across a wide range of both physiological and pathological systems and models.