Does Autophagy Mediate Cardiac Myocyte Death During Stress?

Abstract

Although autophagy generally promotes survival of cardiac myocytes, it can also promote cardiac myocyte death under some conditions. Here, we describe how activation of autophagy leads to death of cardiac myocytes, introduce autosis as a novel and unique form of cell death by autophagy, and discuss the functional significance of autophagic cell death in cardiac myocytes. Autophagy is an evolutionally conserved mechanism for the degradation of cellular components and organelles by lysosomes. Because autophagy is capable of eliminating large protein aggregates and even damaged organelles, it is a unique component of cellular quality control mechanisms. Autophagy also plays an important role in the maintenance of cellular energetics by recycling amino acids and fatty acids for ATP production. One can speculate that these properties of autophagy are particularly advantageous in terminally differentiated cardiac myocytes because protein aggregates and damaged intracellular organelles are not diluted through cell division in these cells and cardiac myocytes have especially high energetic demands. Consistent with these functions, a large number of studies have supported the notion that autophagy is protective in the heart at baseline and in response to stress.1 However, strong evidence also exists that the activation of autophagy in some situations induces cell death. For example, cardiac myocyte death is attenuated by interventions that inhibit activation of autophagy in some models of ischemia/reperfusion,2 pressure overload,3 doxorubicin-induced cardiomyopathy,4 and excessive mitophagy in response to activation of Parkin.5 Nevertheless, the cell-death–promoting effects of autophagy in the heart remains controversial,6,7 in part, because of technical issues (see below) and because of the general belief that autophagy is solely an adaptive mechanism. Here, we discuss the induction of cardiac myocyte death by autophagy in the heart in particular pathological conditions. Autophagic cell death has been described as massive cytoplasmic vacuolization …