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. 2008 Oct;4(7):932-5.
doi: 10.4161/auto.6756. Epub 2008 Oct 8.

The heart of autophagy: deconstructing cardiac proteotoxicity

Beverly A Rothermel  1 , Joseph A Hill
Affiliations

The heart of autophagy: deconstructing cardiac proteotoxicity

Beverly A Rothermel et al. Autophagy. 2008 Oct.

Abstract

The heart is capable of robust structural remodeling, sometimes improving performance and sometimes leading to failure. Recent studies have uncovered a critical role for autophagy in disease-related remodeling of the cardiomyocyte. We have shown previously that hemodynamic load elicits a maladaptive autophagic response in cardiomyocytes which contributes to disease progression. In a recent study, we went on to demonstrate that protein aggregation is a proximal event triggering autophagic clearance mechanisms. The ubiquitin-proteasome-dependent pathways of protein clearance are similarly activated in parallel with processing of stress-induced protein aggregates into aggresomes and clearance through autophagy. These findings in the setting of pressure overload contrast with protein aggregation occurring in a model of protein chaperone malfunction in myocytes, where activation of autophagy is beneficial, antagonizing disease progression. Our findings situate heart disease stemming from environmental stress in the category of proteinopathy and raise important new questions regarding molecular events that elicit adaptive and maladaptive autophagy.

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Figures

Figure 1
Figure 1
Working model of the cellular response to proteotoxicity in cardiomyocytes. Misfolded proteins can arise as a consequence of either environmental cardiac stress or inherited genetic mutation. Accumulated proteins aggregate into soluble complexes that are then transported along microtubules toward the MTOC to form insoluble, caged aggresomes. Proteasomal and autophagic pathways are activated in parallel, targeting different but overlapping sets of substrates. Soluble aggregates are thought to be the toxic species and may induce a specialized form of autophagy called mitophagy by promoting MPT. MPT can also occur in response to aggregate-independent signals occurring in stressed myocardium. The pathophysiological consequences of cardiac autophagy likely depend upon both the rate of flux through these pathways and the cellular components being degraded.
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