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Review
. 2014 Jun:71:3-10.
doi: 10.1016/j.yjmcc.2013.12.015. Epub 2013 Dec 28.

Proteotoxicity: an underappreciated pathology in cardiac disease

Marco Sandri  1 , Jeffrey Robbins  2
Affiliations
Review

Proteotoxicity: an underappreciated pathology in cardiac disease

Marco Sandri et al. J Mol Cell Cardiol. 2014 Jun.

Abstract

In general, in most organ systems, intracellular protein homeostasis is the sum of many factors, including chromosomal state, protein synthesis, post-translational processing and transport, folding, assembly and disassembly into macromolecular complexes, protein stability and clearance. In the heart, there has been a focus on the gene programs that are activated during pathogenic processes, but the removal of damaged proteins and organelles has been underappreciated as playing an important role in the pathogenesis of heart disease. Proteotoxicity refers to the adverse effects of damaged or misfolded proteins and even organelles on the cell. At the cellular level, the ultimate outcome of uncontrolled or severe proteotoxicity is cell death; hence, the pathogenic impact of proteotoxicity is maximally manifested in organs with no or very poor regenerative capability such as the brain and the heart. Evidence for increased cardiac proteotoxicity is rapidly mounting for a large subset of congenital and acquired human heart disease. Studies carried out in animal models and in cell culture have begun to establish both sufficiency and, in some cases, the necessity of proteotoxicity as a major pathogenic factor in the heart. This dictates rigorous testing for the efficacy of proteotoxic attenuation as a new strategy to treat heart disease. This review article highlights some recent advances in our understanding of how misfolded proteins can injure and are handled in the cell, examining the emerging evidence for targeting proteotoxicity as a new therapeutic strategy for heart disease. This article is part of a Special Issue entitled "Protein Quality Control, the Ubiquitin Proteasome System, and Autophagy."

Keywords: Autophagy; Lysosome; Protein.

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Figures

Figure 1
Figure 1
Signalling pathways that control the expression of the ubiquitin ligases in striated muscles. In red are depicted the hormones/cytokines that have a catabolic action while in green are underlined the anabolic ones.
Figure 2
Figure 2
Striated muscle regulation of macroautophagy, microautophagy and chaperone-mediated autophagy (CMA). The different colors underline modules describing the critical steps in the three types of autophagy. The different modules are: autophagosome formation, selective autophagic removal of mitochondria (mitophagy), autophagosome docking, direct glycogen uptake from lysosomes and removal of unfolded/misfolded proteins containing a KFERQ sequence. The dotted lines point to mechanisms that are not yet known. FOXO transcription factors are master regulators of several modules in macroautophagy.
Figure 3
Figure 3
The initial stages of vesicle elongation in macroautophagy. A. Only the initial stages are shown, focusing on the seminal role played by Atg7 in the process, where it intersects with the two possible pathways. The first pathway (top) occurs through the direct interaction of Atg12 with Atg5. This interaction requires the E1-like activity of Atg7. The second pathway involves the addition of phosphotidylethanolamine (PE, shown lower left) to LC3-I, the mammalian homologue of the yeast protein, Atg8. This process is mediated by a protease, Atg4 followed by Atg7’s E1-like enzymatic activity to add PE to LC3-I, coupled with the E2-like activity of Atg3. B. Electron micrograph of a cardiomyocyte derived from the heart of mouse that overexpresses (approximately 10-fold) Atg7. Immediately apparent are elaborated, linear membranes. These structures do not affect cardiac function during the animal’s lifetime [94].
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