Protein Quality Control and Metabolism: Bidirectional Control in the Heart

The prevalence of heart disease, especially heart failure, continues to increase, and cardiovascular disease remains the leading cause of death worldwide. As cardiomyocytes are essentially irreplaceable, protein quality control is pivotal to cellular homeostasis and, ultimately, cardiac performance. Three evolutionarily conserved mechanisms—autophagy, the unfolded protein response, and the ubiquitin-proteasome system—act in concert to degrade misfolded proteins and eliminate defective organelles. Recent advances have revealed that these mechanisms are intimately associated with cellular metabolism. Going forward, comprehensive understanding of the role of protein quality control mechanisms in cardiac pathology will require integration of metabolic pathways and metabolic control. Wang and Hill review bidirectional cross-talk between protein quality control mechanisms within the cardiac myocyte, including autophagy, the unfolded protein response (UPR), and the ubiquitin-proteasome system, and cardiac metabolism. They discuss implications in cardiovascular physiology and pathophysiology and highlight the intricate interplay between these critical pathways.