The term autophagy, or “self-eating”, refers to the processes by which cells deliver cytoplasmic constituents to lysosomes for degradation. Autophagy provides biosynthetic precursors and energy sources to sustain metabolism and cell growth and prevent the accumulation of toxic components. These processes are invoked in response to stressors, including changing nutrient conditions, damage to organelles, intracellular pathogens, and accumulation of reactive oxygen species, among others, in order to maintain cellular homeostasis. Autophagy becomes insufficient with age and is perturbed in multiple disease states; consequently, pathogenic aberrations in autophagy have emerged as a major focus in the development of novel therapeutic strategies. Reviews in this series detail specific autophagic mechanisms; the role of autophagy in cardiovascular disease, cancer, neurodegeneration, lifespan, and the immune system; and methods to develop autophagy-centered therapeutic modalities.
Autophagy (“self-eating”) constitutes one of the most spectacular yet subtly regulated phenomena in cell biology. Similarly to cell division, differentiation, and death, autophagy is perturbed in multiple diseases, in that excessive or deficient autophagy may contribute to pathogenesis. Numerous attempts have been launched to identify specific inducers or inhibitors of autophagy and to use them for the therapeutic correction of its deregulation. At present, several major disease categories (including but not limited to age-related, cardiovascular, infectious, neoplastic, neurodegenerative, and metabolic pathologies) are being investigated for pathogenic aberrations in autophagy and their pharmacologic rectification. Driven by promising preclinical results, several clinical trials are exploring autophagy as a therapeutic target.
Defects in autophagy have been linked to a wide range of medical illnesses, including cancer as well as infectious, neurodegenerative, inflammatory, and metabolic diseases. These observations have led to the hypothesis that autophagy inducers may prevent or treat certain clinical conditions. Lifestyle and nutritional factors, such as exercise and caloric restriction, may exert their known health benefits through the autophagy pathway. Several currently available FDA-approved drugs have been shown to enhance autophagy, and this autophagy-enhancing action may be repurposed for use in novel clinical indications. The development of new drugs that are designed to be more selective inducers of autophagy function in target organs is expected to maximize clinical benefits while minimizing toxicity. This Review summarizes the rationale and current approaches for developing autophagy inducers in medicine, the factors to be considered in defining disease targets for such therapy, and the potential benefits of such treatment for human health.
Beth Levine, Milton Packer, Patrice Codogno
mTOR, a serine/threonine kinase, is a master regulator of cellular metabolism. mTOR regulates cell growth and proliferation in response to a wide range of cues, and its signaling pathway is deregulated in many human diseases. mTOR also plays a crucial role in regulating autophagy. This Review provides an overview of the mTOR signaling pathway, the mechanisms of mTOR in autophagy regulation, and the clinical implications of mTOR inhibitors in disease treatment.
Young Chul Kim, Kun-Liang Guan
Autophagy is a well-conserved catabolic process essential for cellular homeostasis. First described in yeast as an adaptive response to starvation, this pathway is also present in higher eukaryotes, where it is triggered by stress signals such as damaged organelles or pathogen infection. Autophagy is characterized at the cellular level by the engulfment of portions of the cytoplasm in double-membrane structures called autophagosomes. Autophagosomes fuse with lysosomes, resulting in degradation of the inner autophagosomal membrane and luminal content. This process is coordinated by complex molecular systems, including the ATG8 ubiquitin–like conjugation system and the ATG4 cysteine proteases, which are implicated in the formation, elongation, and fusion of these autophagic vesicles. In this Review, we focus on the diverse functional roles of the autophagins, a protease family formed by the four mammalian orthologs of yeast Atg4. We also address the dysfunctional expression of these proteases in several pathologic conditions such as cancer and inflammation and discuss potential therapies based on their modulation.
Álvaro F. Fernández, Carlos López-Otín
Autophagy is a survival-promoting pathway that captures, degrades, and recycles intracellular proteins and organelles in lysosomes. Autophagy preserves organelle function, prevents the toxic buildup of cellular waste products, and provides substrates to sustain metabolism in starvation. Although in some contexts autophagy suppresses tumorigenesis, in most contexts autophagy facilitates tumorigenesis. Cancers can upregulate autophagy to survive microenvironmental stress and to increase growth and aggressiveness. Mechanisms by which autophagy promotes cancer include suppressing induction of the p53 tumor suppressor protein and maintaining metabolic function of mitochondria. Efforts to inhibit autophagy to improve cancer therapy have thereby attracted great interest.
Autophagy is a catabolic process mediated by incorporation of cellular material into cytosolic membrane vesicles for lysosomal degradation. It is crucial for maintaining cell viability and homeostasis in response to numerous stressful conditions. In this Review, the role of autophagy in both normal biology and disease is discussed. Emphasis is given to the interplay of autophagy with nutrient signaling through the ULK1 autophagy pre-initiation complex. Furthermore, related cellular processes utilizing components of the canonical autophagy pathway are discussed due to their potential roles in nutrient scavenging. Finally, the role of autophagy in cancer and its potential as a cancer therapeutic target are considered.
Xuejun Jiang, Michael Overholtzer, Craig B. Thompson
Autophagy is an important intracellular catabolic mechanism critically involved in regulating tissue homeostasis. The implication of autophagy in human diseases and the need to understand its regulatory mechanisms in mammalian cells have stimulated research efforts that led to the development of high-throughput screening protocols and small-molecule modulators that can activate or inhibit autophagy. Herein we review the current landscape in the development of screening technology as well as the molecules and pharmacologic agents targeting the regulatory mechanisms of autophagy. We also evaluate the potential therapeutic application of these compounds in different human pathologies.
Helin Vakifahmetoglu-Norberg, Hong-guang Xia, Junying Yuan
Cardiovascular disease is the leading cause of death worldwide. As such, there is great interest in identifying novel mechanisms that govern the cardiovascular response to disease-related stress. First described in failing hearts, autophagy within the cardiovascular system has been widely characterized in cardiomyocytes, cardiac fibroblasts, endothelial cells, vascular smooth muscle cells, and macrophages. In all cases, a window of optimal autophagic activity appears to be critical to the maintenance of cardiovascular homeostasis and function; excessive or insufficient levels of autophagic flux can each contribute to heart disease pathogenesis. In this Review, we discuss the potential for targeting autophagy therapeutically and our vision for where this exciting biology may lead in the future.
Sergio Lavandero, Mario Chiong, Beverly A. Rothermel, Joseph A. Hill
Most neurodegenerative diseases that afflict humans are associated with the intracytoplasmic deposition of aggregate-prone proteins in neurons. Autophagy is a powerful process for removing such proteins. In this Review, we consider how certain neurodegenerative diseases may be associated with impaired autophagy and how this may affect pathology. We also discuss how autophagy induction may be a plausible therapeutic strategy for some conditions and review studies in various models that support this hypothesis. Finally, we briefly describe some of the signaling pathways that may be amenable to therapeutic targeting for these goals.
Rebecca A. Frake, Thomas Ricketts, Fiona M. Menzies, David C. Rubinsztein
The broad immunologic roles of autophagy span innate and adaptive immunity and are often manifested in inflammatory diseases. The immune effects of autophagy partially overlap with its roles in metabolism and cytoplasmic quality control but typically expand further afield to encompass unique immunologic adaptations. One of the best-appreciated manifestations of autophagy is protection against microbial invasion, but this is by no means limited to direct elimination of intracellular pathogens and includes a stratified array of nearly all principal immunologic processes. This Review summarizes the broad immunologic roles of autophagy. Furthermore, it uses the autophagic control of
Vojo Deretic, Tomonori Kimura, Graham Timmins, Pope Moseley, Santosh Chauhan, Michael Mandell
Life and health span can be prolonged by calorie limitation or by pharmacologic agents that mimic the effects of caloric restriction. Both starvation and the genetic inactivation of nutrient signaling converge on the induction of autophagy, a cytoplasmic recycling process that counteracts the age-associated accumulation of damaged organelles and proteins as it improves the metabolic fitness of cells. Here we review experimental findings indicating that inhibition of the major nutrient and growth-related signaling pathways as well as the upregulation of anti-aging pathways mediate life span extension via the induction of autophagy. Furthermore, we discuss mounting evidence suggesting that autophagy is not only necessary but, at least in some cases, also sufficient for increasing longevity.
Frank Madeo, Andreas Zimmermann, Maria Chiara Maiuri, Guido Kroemer