Autophagy, lipophagy and lysosomal lipid storage disorders

Abstract

Autophagy is a catabolic process with an essential function in the maintenance of cellular and tissue homeostasis. It is primarily recognised for its role in the degradation of dysfunctional proteins and unwanted organelles, however in recent years the range of autophagy substrates has also been extended to lipids. Degradation of lipids via autophagy is termed lipophagy. The ability of autophagy to contribute to the maintenance of lipo-homeostasis becomes particularly relevant in the context of genetic lysosomal storage disorders where perturbations of autophagic flux have been suggested to contribute to the disease aetiology. Here we review recent discoveries of the molecular mechanisms mediating lipid turnover by the autophagy pathways. We further focus on the relevance of autophagy, and specifically lipophagy, to the disease mechanisms. Moreover, autophagy is also discussed as a potential therapeutic target in several key lysosomal storage disorders.

Breaking fat: The regulation and mechanisms of lipophagy

“…Alternatively, protein modification via polyubiquitination may serve as a lipophagy-promoting signal. For example, interactions between ancient ubiquitous protein 1 (AUP1) and the E2 ubiquitin conjugase G2 at the LD surface may promote the tagging of droplets for degradation [64–66]. Further work will be required to precisely define the signals initiating and regulating the autophagic turnover of LDs.…”

Zika Fetal Neuropathogenesis: Etiology of a Viral Syndrome

“…Autophagy is a normal cellular process wherein the cell digests large protein complexes or intracellular pathogens and has been shown to play an important role in the maintenance of stem cells [225]. This process can provide a way for a cell to recycle materials under conditions of starvation or as a way to respond to intracellular infection [226]. Studies of cells infected by ZIKV and other flaviviruses have shown an increase in the levels of autophagy [168,227–229].…”

“…However, in the case of ZIKV, this mechanism may help replication and spread by the virus once initial infection has been established and could increase the susceptibility of nearby myeloid cells. Multiple lines of research suggest a role for autophagy in neurodegenerative diseases, which indicates that these ZIKV-mediated changes in autophagy may also be involved in the observed neuropathic effects [226,230,231]. Pharmacologic inhibition of autophagy is associated with inhibition of ZIKV replication in a variety of cell types, including human astrocytes [7,168].…”

The Evolving Functions of Autophagy in Ocular Health: A Double-edged Sword

“…The degradative phase of autophagy occurs in lysosomes, to which cytoplasmic cargoes are delivered 28. Defective lysosomal degradation is the major cause of lipofuscinogenesis.…”