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Review
.2015 Feb 3;21(2):215-226.
doi: 10.1016/j.cmet.2015.01.016.

Protein quality control and metabolism: bidirectional control in the heart

Affiliations
Review

Protein quality control and metabolism: bidirectional control in the heart

Zhao V Wang et al. Cell Metab..

Abstract

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.

Copyright © 2015 Elsevier Inc. All rights reserved.

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Conflict of interest statement

Conflicts of Interest

We declare no conflicts of interest.

Figures

Figure 1
Figure 1. Protein quality control and cardiac metabolism in heart disease
Disease-related stress on the myocardium triggers increased demand for protein folding and protein damage. These events, in turn, activate the UPR, autophagy, and the UPS. Glucose and free fatty acid (FFA) are the major nutrients supporting energy production in the myocardium. Recent insights have uncovered complex interplay between these two major cellular processing, including bidirectional signaling, transcriptional control, and substrate provision.
Figure 2
Figure 2. The autophagy pathway
Autophagy is an evolutionarily conserved self-eating process. Autophagy is dynamic, involving multiple steps of initiation, vesicle nucleation, elongation/expansion and fusion. Engulfed cargo is digested by acid hydrolases from the lysosome, and degraded components are released into the cytosol to meet energetic demand. Several complexes participate in autophagosome formation at various steps, including an initiation complex, the class III PI3K complex, and two ubiquitin-like systems.
Figure 3
Figure 3. The unfolded protein response
The unfolded protein response (UPR) is an adaptive mechanism to cope with protein folding stress in the endoplasmic reticulum (ER). Misfolded proteins in the ER occupy the ER-resident chaperone BiP. Three signal transducers of the UPR are induced by a variety of mechanisms to attenuate global protein translation, and stimulate expression of genes coding for proteins involved in protein chaperoning, autophagy, ER-associated protein degradation, and metabolic regulation. In the setting of unremitting stress, cell death ensues to eliminate terminally defective cells. nATF6, nuclear ATF6.
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