Recent progress in research on molecular mechanisms of autophagy in the heart

Abstract

Dysregulation of autophagy, an evolutionarily conserved process for degradation of long-lived proteins and organelles, has been implicated in the pathogenesis of human disease. Recent research has uncovered pathways that control autophagy in the heart and molecular mechanisms by which alterations in this process affect cardiac structure and function. Although initially thought to be a nonselective degradation process, autophagy, as it has become increasingly clear, can exhibit specificity in the degradation of molecules and organelles, such as mitochondria. Furthermore, it has been shown that autophagy is involved in a wide variety of previously unrecognized cellular functions, such as cell death and metabolism. A growing body of evidence suggests that deviation from appropriate levels of autophagy causes cellular dysfunction and death, which in turn leads to heart disease. Here, we review recent advances in understanding the role of autophagy in heart disease, highlight unsolved issues, and discuss the therapeutic potential of modulating autophagy in heart disease.

Keywords: autophagy; autosis; mitophagy; protein quality control.

Fig. 1.

Schematic model of the molecular mechanisms regulating mitophagy. There are 2 signaling pathways for selective activation of mitophagy: the phosphatase and tensin homolog-induced putative kinase 1 (PINK1)-Parkin-mediated pathway and the mitophagic-receptor [Bcl-2/adenovirus E1B 19 kDa-interacting protein 3 (BNIP3) and BNIP-like (NIX)]-mediated pathway (see text for details and definitions of abbreviations). There are also several systems for suppression of mitophagy. Arrows denote stimulation, and T-shaped indicators denote inhibition. U, ubiquitin; ΔΨm, mitochondrial membrane potential.

Fig. 2.

Schematic model of Beclin-1, B-cell lymphoma-extra large (Bcl-2/xL), and mammalian sterile 20-like kinase 1 (Mst1) interactions in the regulation of autophagy in the heart. Mst1 phosphorylates Beclin-1 at Thr¹⁰⁸, leading to enhancement of Beclin-1-Bcl-2/xL binding, Beclin-1 homodimer formation, and inhibition of vacuolar protein sorting 34 (Vps34) kinase activity, thereby suppressing autophagosome formation. Activation of Mst1 downregulates autophagy below physiological levels and suppresses protein quality control, contributing to cardiac dysfunction (see text for details and definitions of abbreviations). Arrows denote stimulation, and T-shaped indicators denote inhibition. P, phosphate; CCD, coiled coil domain; DAPK, death-associated protein kinase.

Fig. 3.

Schematic model of the major pathways in the regulation of the autophagic machinery. There are 3 different types of autophagic pathways: macroautophagy, microautophagy, and chaperone-mediated autophagy. In macroautophagy, there are 2 subtypes of autophagic pathways: conventional and alternative macroautophagy (see text for details and definitions of abbreviations). ULK1, unc-51-like autophagy-activating kinase 1; Flp-200, FAK family-interacting protein of 200 kDa; Rab9, Rab family GTPase 9; PE, phosphatidylethanolamine.