Regulation of Mammalian Autophagy in Physiology and Pathophysiology

Abstract

(Macro)autophagy is a bulk degradation process that mediates the clearance of long-lived proteins and organelles. Autophagy is initiated by double-membraned structures, which engulf portions of cytoplasm. The resulting autophagosomes ultimately fuse with lysosomes, where their contents are degraded. Although the term autophagy was first used in 1963, the field has witnessed dramatic growth in the last 5 years, partly as a consequence of the discovery of key components of its cellular machinery. In this review we focus on mammalian autophagy, and we give an overview of the understanding of its machinery and the signaling cascades that regulate it. As recent studies have also shown that autophagy is critical in a range of normal human physiological processes, and defective autophagy is associated with diverse diseases, including neurodegeneration, lysosomal storage diseases, cancers, and Crohn's disease, we discuss the roles of autophagy in health and disease, while trying to critically evaluate if the coincidence between autophagy and these conditions is causal or an epiphenomenon. Finally, we consider the possibility of autophagy upregulation as a therapeutic approach for various conditions.

Association of the K153R polymorphism in the myostatin gene and extreme longevity

“…The central component of the mTOR pathway, the TOR kinase, forms two functionally different complexes: TOR complex (TORC) 1 and TORC2, with TORC1 promoting growth by positively regulating S6 kinase (Fenton and Gout 2011) and TORC2 activating the pro-survival Akt kinase of the insulin/insulin-like growth factor signalling pathway (Cybulski and Hall 2009;Sparks and Guertin 2010). For instance, under starvation conditions, TORC1 is responsible for up-regulating autophagy, a process that generates energy by degrading portions of the cytoplasm (Neufeld 2010;Ravikumar et al 2010). A number of studies have demonstrated that myostatin acts as a negative regulator of mTOR-directed signalling, which is consistent with its inhibitory effect on protein synthesis (Amirouche et al 2009;Langley et al 2002;Lipina et al 2010;McFarlane et al 2006;Rios et al 2004;Sartori et al 2009;Trendelenburg et al 2009) and more specifically on protein translation in skeletal muscle (Trendelenburg et al 2009).…”

Cell death in the pathogenesis and progression of heart failure

“…1). This evolutionary conserved catabolic pathway plays an essential role during mammalian development and differentiation [19,20]. Autophagy is usually induced under various stress conditions, including starvation, OS, I/R and pathogen infections, and helps organisms to fight against degenerative, infectious, inflammatory and neoplastic disorders.…”

Identification of autophagy signaling network that contributes to stroke in the ischemic rodent brain via gene expression

“…Moreover, variations within NFKB1 and IκBα can potentially influence the function of NF-κB [58] and in turn the autophagy process. As autophagy participates in the neuronal death and functional loss induced ischemia/reperfusion injury [59][60][61] , genes involved in autophagy would be associated with cerebral ischemia.…”