Autophagy and disease: unanswered questions

Abstract

Autophagy is a process in which intracellular components and dysfunctional organelles are delivered to the lysosome for degradation and recycling. Autophagy has various connections to a large number of human diseases, as its functions are essential for cell survival, bioenergetic homeostasis, organism development, and cell death regulation. In the past two decades, substantial effort has been made to identify the roles of autophagy in tumor suppression and promotion, neurodegenerative disorders, and other pathophysiologies. This review summarizes the current advances and discusses the unanswered questions in understanding the involvement of autophagy in pathogenic mechanisms of disease, primarily focusing on cancer and neurodegenerative diseases.

Fig. 1. Schematic model for macroautophagy and PINK1-PRKN-mediated mitophagy.

Macroautophagy initiation occurs in response to cellular stresses. The phagophore nucleates and expands to sequester unwanted organelles and macromolecules and forms a double-membrane structure named the autophagosome. The outer membrane of the autophagosome fuses with a lysosome to deliver the cargo to the newly formed autolysosome for degradation. The breakdown products are further recycled following the release from permeases present in the lysosome/autolysosome membrane. The bottom scheme represents nonselective macroautophagy with the feature of random sequestration of cytoplasm. The top scheme depicts PINK1-PRKN-mediated mitophagy. Under normal conditions, PINK1 is cleaved within mitochondria in healthy mitochondria, and retrotranslocates to the cytosol for proteasomal degradation. When mitochondria damage occurs, mitophagy is induced. First, PINK1 is stabilized on the outer membrane and phosphorylates ubiquitin and PRKN separately. By this action, PRKN is recruited to the mitochondria surface and further ubiquitinates outer mitochondrial membrane (OMM) proteins. Ubiquitin is able to recruit more PRKN to form a feedback loop. Phosphorylated ubiquitin also recruits mitophagy receptors such as CALCOCO2/NDP52 and OPTN, which bind to phagophore-attached LC3, stimulating the engulfment of abnormal mitochondria in a phagophore.

Fig. 2. Schematic model of chaperone-mediated autophagy.

In chaperone-mediated autophagy, cytosolic proteins with a KFERQ motif are first recognized by HSPA8. The substrate-chaperone complex binds to a LAMP2A monomer. Subsequently, substrate translocation occurs via substrate unfolding and LAMP2A multimerization. Eventually, substrates are degraded in the lysosome and the resulting products are reused in the cell.