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.

Activation of FMS ‐like tyrosine kinase 3 protects against isoprenaline‐induced cardiac hypertrophy by improving autophagy and mitochondrial dynamics

“…In this study, we found that ISO enhanced the expression of autophagy markers LC3II and p62 in cardiomyocytes in vivo and in vitro, while Flt3 activation overtly normalized these changes. Since p62 is an autophagy receptor that interacts with phagophores in the LC3 domain, in turn, interacting with the ubiquitin‐proteasome system to mediate autophagosome degradation, 29 p62 could be used to monitor autophagy flux. Therefore, Flt3 activation reduced ISO‐induced accumulation of p62, suggesting the restoration of autophagic flux.…”

First Evidence of the Expression and Localization of Prothymosin α in Human Testis and Its Involvement in Testicular Cancers

“…It is worth noting the crosstalk between apoptosis and autophagy during cancer progression. Noticeably, apoptosis downregulation is one of the most typical causes/manifestations of cancer; on the contrary, autophagy plays a double-edged sword in cancer biology: in the initial stages of cancer progression, it removes damaged cytosolic organelles and contents (as mutated DNA), acting as tumor suppressor [ 68 ]; conversely, autophagy can promote cancer cells growth and progression, functioning as an adaptive metabolic response, through recycling macromolecules, in hostile conditions, as poor vascularization, nutrient deprivation, and hypoxia in solid tumors [ 69 ].…”

The Role of Intermittent Fasting in the Management of Nonalcoholic Fatty Liver Disease: A Narrative Review

“…IF interventions appeared to confer health benefits independent of energy intake ( Figure 1 ) [ 2 , 3 , 23 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 ]. For example, in two separate trials of overweight women, participants lost the same amount of weight during a 6-month period whether they followed an IF intervention or a 25% energy-restricted diet.…”

“… Potential mechanisms of action for effects of intermittent fasting in NAFLD. Obesity is a risk factor for NAFLD [ 3 ] and is associated with low-grade inflammation [ 2 , 32 ] marked by presence of increased white adipose tissue, increased pro-inflammatory M1 macrophages, decreased anti-inflammatory M2 macrophages [ 2 ], formation of new blood vessels (angiogenesis), increased gut microbial dysbiosis [ 40 ], and changes in autophagy-related physiological processes [ 41 ]. Intermittent fasting may play a role in circadian rhythm modulation [ 34 , 37 ], adipose tissue plasticity [ 35 , 36 ], adipokine production [ 23 ], and gut microbiome [ 23 , 33 ] through increased SCFA production [ 38 , 39 ] and autophagy [ 31 ], with potential to reverse inflammation, metabolic dysfunction, and impaired immune system regulation associated with NAFLD.…”