Autophagy in health and disease: From molecular mechanisms to therapeutic target

Abstract

Macroautophagy/autophagy is an evolutionally conserved catabolic process in which cytosolic contents, such as aggregated proteins, dysfunctional organelle, or invading pathogens, are sequestered by the double-membrane structure termed autophagosome and delivered to lysosome for degradation. Over the past two decades, autophagy has been extensively studied, from the molecular mechanisms, biological functions, implications in various human diseases, to development of autophagy-related therapeutics. This review will focus on the latest development of autophagy research, covering molecular mechanisms in control of autophagosome biogenesis and autophagosome-lysosome fusion, and the upstream regulatory pathways including the AMPK and MTORC1 pathways. We will also provide a systematic discussion on the implication of autophagy in various human diseases, including cancer, neurodegenerative disorders (Alzheimer disease, Parkinson disease, Huntington's disease, and Amyotrophic lateral sclerosis), metabolic diseases (obesity and diabetes), viral infection especially SARS-Cov-2 and COVID-19, cardiovascular diseases (cardiac ischemia/reperfusion and cardiomyopathy), and aging. Finally, we will also summarize the development of pharmacological agents that have therapeutic potential for clinical applications via targeting the autophagy pathway. It is believed that decades of hard work on autophagy research is eventually to bring real and tangible benefits for improvement of human health and control of human diseases.

Keywords: SARS‐CoV‐2; autophagy; cancer; cardiovascular diseases; metabolic diseases; neurodegenerative diseases.

FIGURE 1

Molecular mechanisms in control of autophagy. Autophagy could be induced by various stress conditions such as amino starvation, glucose depletion, and others. The common target of these signaling pathways is the ULK1 complex. Under normal condition, MTORC1 inhibits ULK1 via phosphorylation. Under stress condition, MTORC1 is suppressed, leading to activation and recruitment of the ULK1 complex to PAS. ULK1 further activates PI3KC3–C1, resulting in generation of PtdIns3P (PI3P). WIPI2 then binds to PtdIns3P and further recruits ATG12–ATG5–ATG16L1 to the phagophore to mediate the lipidation of mATG8, which is essential for elongation and closure of the phagophore membrane. Additionally, the ATG9 vesicles are believe to supply membrane source, which also contributes to elongation of the phagophore membrane. Autophagosome–lysosome fusion is mediated by specific SNARE proteins, the HOPS tethering complex, small GTPases such as RAB7 and their effector PLEKHM1, and other factors detailed in the main text. The molecular mechanisms of these factors in autophagosome–lysosome fusion are discussed in the main text

FIGURE 2

The implication of autophagy in carcinogenesis. Autophagy may act as a powerful barrier to prevent transformation of normal cells into tumor cells. Upon autophagy deficiency, misfold proteins or dysfunctional organelles accumulates, which may cause genomic defects that accompanies transformation. On the other hand, autophagy acts as a mechanism for transformed cells to get adapted to various cellular stress responses, promote metastasis, and maintain tumor stemness

FIGURE 3

The mechanisms and therapeutic targets of autophagy in neurodegenerative diseases. An increasing number of genes associated with neurodegenerative diseases, especially AD, PD, HD, and ALS, act at different steps throughout the autophagic process. Their proposed sites of action, as well as associated neurodegenerative diseases are indicated. The protein aggregates, supposed to be degraded by the autophagy–lysosome pathway, accumulate and contribute to neurodegenerative diseases when autophagy is defective. AD, Alzheimer's disease; PD, Parkinson's disease; HD, Huntington's disease; ALS, Amyotrophic lateral sclerosis

FIGURE 4

Pathogenesis of diabetes and the implication of autophagy in diabetes. (A) The schematic diagram of type I diabetes and type II diabetes; (B) the effects of insulin resistance and insulin secretion on β‐cell autophagy. Various stress and inflammatory responses to lipotoxicity can induce polyubiquitination of proteins and cytoplasmic aggregation of damaged organelles in β‐cells. Impaired autophagy leads to cellular dysfunction, affects insulin secretion, results in insulin resistance, and promotes diabetes progression

FIGURE 5

Targeting the autophagy‐lysosome pathway as novel therapeutic strategies for COVID‐19. The replication cycle of SARS‐CoV‐2 consists of six consecutive steps, as well as the cross‐talks of this cycle with the autophagy–lysosome pathway are presented. The red boxes indicate that the lysosomotropic agents targeting the autophagy–lysosome pathway are under development as therapeutics against COVID‐19

FIGURE 6

The protective effects of autophagy on cardiovascular diseases. Autophagy is essential for maintaining the intracellular homeostasis of cardiomyocytes under both basal and stress conditions. In response to cardiac ischemia/reperfusion, autophagy acts as a survival mechanism for replenishment of metabolic substrates and removal of damaged organelle such as damaged mitochondria. Impairment of autophagy results in cardiomyocyte cell death and exacerbates ischemia/reperfusion injury. Dysregulation of autophagy is also related to other cardiovascular diseases such as cardiac hypertrophy and dilated cardiomyopathy

FIGURE 7

Systemic antiaging effects of autophagy. Autophagy may increase organismal fitness by eliminating protein aggregates, damaged organelles, apoptotic corpses. In addition, autophagy may contribute to the clearance of intracellular pathogens and enhancing the function of antigen‐presenting cells to attenuate age‐related dysfunctions and extend lifespan

FIGURE 8

Autophagy activators and inhibitors. Mechanistic targets of autophagy activators and inhibitors. The major targets and related compounds of autophagy activation (arrows and boxes in red) and inhibition (arrows and boxes in blue) have been demonstrated