Cardiomyocyte autophagy: metabolic profit and loss

Abstract

Cardiovascular disease remains the leading cause of morbidity and mortality worldwide, even despite recent scientific and technological advances and comprehensive preventive strategies. The cardiac myocyte is a voracious consumer of energy, and alterations in metabolic substrate availability and consumption are hallmark features of these disorders. Autophagy, an evolutionarily ancient response to metabolic insufficiency, has been implicated in the pathogenesis of a wide range of heart pathologies. However, the precise role of autophagy in these contexts remains obscure owing to its multifarious actions. Here, we review recently derived insights regarding the role of autophagy in cardiac hypertrophy and heart failure, highlighting its effects on metabolism.

Fig. 1

The autophagy pathway. To induce autophagy, a dynamic and highly regulated process, the serine/threonine kinase complex ATG1/ATG13/ATG17 is activated when the inhibitory effects of TOR are removed. The lipid kinase VPS34 and anchoring component VPS15 stimulate isolation membrane nucleation. Then, two ubiquitin-like conjugation systems, ATG12 and LC3, contribute to the expansion of the autophagosome. After fusion with a single membrane lysosome, the engulfed cytoplasmic materials are degraded by acid hydrolases within the autolysosome, and nutrients are released to the cytosol for recycling

Fig. 2

The interplay between glucose metabolism and autophagy in cardiac hypertrophy. During hypertrophic remodeling, glucose uptake and utilization are increased. In parallel, robust activation of autophagy occurs, contributing to metabolic changes in various ways. Nutrients provided by autophagic degradation can produce glucose-6-phosphate for NAPDH production and glycolysis as well as key intermediate metabolites for macromolecule biosynthesis and ATP production. Thus, up-regulation of both glucose metabolism and autophagy in cardiac hypertrophy foster synergistic crosstalk to fulfill goals of enhanced ATP production and biosynthesis

Fig. 3

Multiple ways in which autophagy participates in metabolic remodeling. Autophagy and lysosomal degradation provide essential nutrients which contribute to energy and biomaterial production. Amino acids may be directly used for new protein synthesis or fueled into the TCA cycle after deamination. Nucleotides can be recycled for new nucleic acid synthesis or to participate in the pentose phosphate pathway (PPP). Sugar moieties from protein/lipid degradation can be channeled to new glycan synthesis or to glucose-6-phosphate for glycolysis. Lipids can feed into the β-oxidation pathway for energy purposes or into the biosynthetic pathway for new membrane generation

Fig. 4

Metabolic functions of autophagy in heart failure. During the progression from adaptive cardiac hypertrophy to decompensated heart failure, autophagy can be induced by accumulation of reactive oxygen species (ROS) and by oxidized and misfolded proteins. Enhancement of autophagic activity, in turn, can target mitochondria selectively (mitophagy) or indiscriminately, thereby negatively impacting ATP production, exacerbating ROS generation, and promoting disease progression

Fig. 5

Metabolic profit and loss of autophagy in cardiac hypertrophy and failure. Basal autophagic activity is essential to maintain cardiomyocyte energy production and cellular homeostasis. The significant increase in autophagy seen during cardiac hypertrophy may contribute to adaptive metabolic remodeling, which, together with enhancement of glucose utilization, plays critical roles in ATP production and macromolecule biosynthesis required for hypertrophic growth. The deterioration of energy status in end-stage heart failure triggers exuberant autophagy, which may target mitochondria for degradation, further impairing both glucose and fatty acid metabolism