Protein Quality Control and Metabolism: Bidirectional Control in the Heart

Abstract

The prevalence of heart disease, especially heart failure, continues to increase, and cardiovascular disease remains the leading cause of death worldwide. As cardiomyocytes are essentially irreplaceable, protein quality control is pivotal to cellular homeostasis and, ultimately, cardiac performance. Three evolutionarily conserved mechanisms – autophagy, the unfolded protein response, and the ubiquitin-proteasome system– act in concert to degrade misfolded proteins and eliminate defective organelles. Recent advances have revealed that these mechanisms are intimately associated with cellular metabolism. Going forward, comprehensive understanding of the role of protein quality control mechanisms in cardiac pathology will require integration of metabolic pathways and metabolic control.

Aging and Autophagy in the Heart

“…Elucidating the molecular mechanisms by which the UPR mt maintains mitochondrial homeostasis and whether the UPR mt acts through autophagy and/or mitophagy in mammalian cardiomyocytes would be interesting and should provide clues for the development of novel interventions to achieve anti-senescence therapy in the heart. It should be noted that endoplasmic reticulum (ER) stress also induces autophagy and a UPR to eliminate misfolded proteins and defective organelles 65 . However, the connection between ER stress and aging is, to date, less well defined than that between the UPR mt and aging.…”

Increasing the Unneddylated Cullin1 Portion Rescues the csn Phenotypes by Stabilizing Adaptor Modules To Drive SCF Assembly

“…aintaining an integrated and functional proteome is crucial for cell survival and development (1). Eukaryotes have evolved two major systems to remove aberrant proteins: the ubiquitin-proteasome system (UPS) and lysosomal degradation system (autophagy) (2).…”

Melatonin protects against chronic intermittent hypoxia-induced cardiac hypertrophy by modulating autophagy through the 5′ adenosine monophosphate-activated protein kinase pathway

“…Moreover, autophagy is an important cellular process and plays a direct role in cardiac hypertrophy. Autophagy is maintained at low levels under normal conditions [33] and is upregulated to ameliorate cardiac hypertrophy and maintain cardiac function and morphology during heart failure and pressure overload [14,15]. Decreased autophagy levels induced by deletion of autophagy protein 5 (ATG5) causes cardiac dysfunction and adverse myocardial hypertrophy [34].…”

“…Moreover, autophagy eliminates unnecessary cells during tissue and organ development [12]. Basal autophagy occurs constitutively in the heart and is substantially upregulated to protect the heart during ischemic cardiomyopathy [13], heart failure [14], and cardiac hypertrophy [14,17]. Impaired autophagy leads to the rapid development of heart failure [16] and promotes cardiac hypertrophy [17].…”