Cardiomyocyte autophagy: remodeling, repairing, and reconstructing the heart

Abstract

Autophagy is an evolutionarily conserved catabolic pathway of lysosome-dependent turnover of damaged proteins and organelles. When nutrients are in short supply, bulk removal of cytoplasmic components by autophagy replenishes depleted energy stores, a process critical for maintaining cellular homeostasis. However, prolonged activation of autophagic pathways can result in cell death. Longstanding evidence has linked the stimulation of lysosomal pathways to pathologic cardiac remodeling and a number of cardiac diseases, including heart failure and ischemia. Only recently, however, has work begun to parse cytoprotective autophagy from autophagy that contributes to disease pathogenesis. Current thinking suggests that the effects of autophagy exist on a continuum, with the eliciting triggers, the duration and amplitude of autophagic flux, and possibly the targeted intra-cellular cargo as critical determinants of the end result. Deciphering how autophagy participates in basal homeostasis of the heart, in aging, and in disease pathogenesis may uncover novel insights with clinical relevance in the treatment of heart disease.

Figure 1

The process of autophagy. A variety of stresses, such as starvation, trigger the autophagy process through the Class III PI3K/Beclin 1 complex. This complex initiates formation of isolated double membranes (the membrane nucleation process) and subsequent membrane elongation. The membrane then fuses on itself, forming the distinctive double-membrane autophagosome. Autophagosomes ultimately fuse with lysosomes, and their cargo is degraded, providing fuel and elemental building blocks to preserve vital cellular functions. ATG—autophagy-related genes; PI3K— phosphatidylinositide-3-kinase.