Regulation of autophagy by Beclin 1 in the heart

• Beclin 1 plays an essential role in mediating autophagy in mammalian cells.
• Gain and loss of function of Beclin 1 affect autophagy and death of heart cells.
• The function of Beclin 1 is inhibited by its interaction with Bcl-2.
• Mst1 phosphorylates n1 and increases Beclin 1–Bcl-2 interaction.

Dysregulation of autophagy in cardiomyocytes is implicated in various heart disease conditions. Beclin 1, a mammalian ortholog of yeast Atg6 and a core component of the autophagy machinery, plays a central role in the regulation of autophagy through activation of Vps34. Beclin 1's ability to activate Vps34 is tightly regulated via transcriptional regulation, miRNA, post-translational modification, and interaction with Beclin 1 binding proteins. Of these mechanisms, binding of Beclin 1 with Bcl-2 family proteins (Bcl-2/XL) that negatively regulate autophagy activity has been shown to be both positively and negatively regulated by various kinases, including DAPK, ROCK1, Mst1 and JNK1, in response to external stimuli. Beclin 1's interaction with Bcl-2/XL also secondarily affects apoptosis through regulation of pro-apoptotic BH3 domain containing proteins. Thus, modulation of Beclin 1 significantly influences both autophagy and apoptosis, thereby deeply affecting the survival and death of cardiomyocytes in the heart. In this review, we discuss the signaling mechanism of autophagy modulation through Beclin 1 and therapeutic potential of Beclin 1 in heart diseases.