Autophagy as a Therapeutic Target
Plenty of evidence points to improvement in the cellular maintenance processes of autophagy (primarily macroautophagy and chaperone-mediated autophagy) as the primary mechanism by which the response to mild stress improves health and extends life. Autophagy recycles broken molecules and damaged structures in the cells. More recycling implies better function, a lesser burden of damage and dysfunction at any given time. This underlies the extension of life span resulting from calorie restriction, for example. Researchers are interested in the development of drugs that mimic these stress responses by artificially upregulating autophagy. mTOR inhibitors achieve this goal, as do other calorie restriction mimetic drugs, but the effects in humans are so far modest, producing effects that, on the whole, compare poorly to the outcome of structured exercise programs, or the practice of calorie restriction itself.
Autophagy refers to a process in which the intracellular components such as abnormal proteins, damaged organelles, foreign pathogens, and other cellular components are degraded via lysosome. This catabolic process is evolutionarily conserved from yeast to mammalian cells. In mammalian cells, autophagy has been traditionally classified into the following three main types, macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA). Among them, macroautophagy is featured by the formation of a unique double-membrane organelle, the autophagosome. In contrast, both microautophagy and CMA bypass autophagosome formation and the cargos are directly delivered to a lysosome.
At present, the majority of the autophagy research is on macroautophagy, or referred as autophagy hereafter in this review. On the other hand, depending on the nature of the cargos, autophagy can be categorized into general/nonselective and selective autophagy. For nonselective autophagy, the cellular cargos are engulfed into the autophagosomes randomly, a process usually induced by general stress conditions such as nutrient starvation. In contrast, selective autophagy refers to selective degradation of specific cargos, and so far, there are many types of selective autophagy being studied, such as mitophagy (selective degradation of mitochondria), endoplasmic reticulum (ER)-phagy (selective degradation of ER), aggrephagy (selective degradation of protein aggregates), and xenophagy (selective degradation of invaded pathogens), just to name a few.
It has been well studied that autophagy have important functions in various biological processes, such as cell survival and cell death, inflammation and immunity, development and differentiation, metabolic homeostasis, and so on. As such, autophagy is known to be closely implicated in the pathogenesis of human diseases. In this review, we will mainly focus on nonselective macroautophagy to provide a systematic discussion on the latest development on the molecular mechanisms, the implication of autophagy in important human diseases including cancer, neurodegeneration, metabolic diseases, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, cardiovascular diseases, and aging. Moreover, we will also discuss the therapeutic potential of targeting autophagy in human diseases. Finally, we will highlight the challenges the autophagy research field is facing and the directions of future study.