Autophagy in immune cell regulation and dysregulation

Autophagy is an ancient pathway required for cell and tissue homeostasis and differentiation. Initially thought to be a process leading to cell death, autophagy is currently viewed as a beneficial catabolic process that promotes cell survival under starvation conditions by sequestering components of the cytoplasm, including misfolded proteins, protein aggregates, and damaged organelles, and targeting them for lysosome-mediated degradation. In this way, autophagy plays a role in maintaining a balance between degradation and recycling of cellular material. The importance of autophagy is underscored by the fact that malfunctioning of this pathway results in neurodegeneration, cancer, susceptibility to microbial infection, and premature aging. Autophagy occurs in almost all cell types, including immune cells. Recent advances in the field suggest that autophagy plays a central role in regulating the immune system at multiple levels. In this review, we focus on recent developments in the area of autophagy-mediated modulation of immune responses.     

Chemotherapy and autophagy-mediated cell death in pancreatic cancer cells

Autophagy is an evolutionarily preserved degradation process of cytoplasmic cellular constituents and plays important physiological roles in human health and disease. It has been proposed that autophagy plays an important role both in tumor progression and in promotion of cancer cell death, although the molecular mechanisms responsible for this dual action of autophagy in cancer have not been elucidated. Pancreatic ductal adenocarcinoma is one of the most aggressive human malignancies with 2–3% five-year survival rate. Its poor prognosis has been attributed to the lack of specific symptoms and early detection tools, and its relatively refractory to traditional cytotoxic agents and radiotherapy. Experimental evidence pointed at autophagy as a pancreatic cancer cell mechanism to survive under adverse environmental conditions, or as a defective programmed cell death mechanism that favors pancreatic cancer cell resistance to treatment. Here, we consider several phenotypical alterations that have been related to increase or decrease the autophagic process in pancreatic tumor cells. We specially review autophagy as a cell death mechanism in response to chemotherapeutic drugs.     

Apoptosis regulation by autophagy gene 5

Autophagy is a cellular process, in which cellular proteins and cytoplasmic organelles are degraded. It reflects the response of a cell to stress or starvation with the primary goal of cell survival. On the other hand, if the autophagic activity is too high, cell death happens, suggesting that this process requires a tight control. Autophagic cell death has often been observed under conditions, in which apoptosis is blocked. Recent studies suggest that autophagy may promote apoptosis and that Bcl-2 cannot block only apoptosis, but also autophagy and autophagic cell death. Here, we discuss recent findings regarding the interrelations between autophagy and apoptosis. In particular, we would like to draw the attention of the readers to Atg5, which exhibits, like Bcl-2, a dual function by modulating both autophagy and apoptosis.     

Impaired quality control of mitochondria: Aging from a new perspective

Mitochondria fulfill a number of essential cellular functions and play a key role in the aging process. Reactive oxygen species (ROS) are predominantly generated in this organelle but next to inducing oxidative damage they act as signaling molecules. Autophagy is regulated by signaling ROS and is known to affect aging as well as neurodegenerative diseases. Many cellular components that influence autophagy are linked to longevity such as members of the sirtuin protein family. Recent studies further link mitochondrial dynamics to the removal of dysfunctional mitochondria by mitophagy, thereby representing a novel mechanism for the quality control of mitochondria. Here we summarize the current views on how mitochondrial function is linked to aging and we propose that quality control of mitochondria has a crucial role in counteracting the aging process.     

Role of programmed cell death in the aging process: an unexplored possibility

The possibility of cell death being a programmed event under neuroendocrine control during aging is discussed. Physiological cell death is currently regarded as a built-in cellular mechanism which can be triggered by extracellular signals. The term 'programmed cell death' is employed when these signals are involved in developmental or adaptive processes. Programmed cell death has a wide incidence throughout the animal kingdom, both during development and reproduction. Consequently, the involvement of such a basic cellular process in aging appears as a plausible possibility. The neuroendocrine system best qualifies as the potential regulator of cell death during aging. First, it is the major regulator of homeostasis and developmental processes in higher organisms. Second, in many instances physiological cell death has been shown to be under control of the neuroendocrine system during development and reproduction. Finally, this system is implied in the decline of several physiological functions during aging. The above considerations point to this unexplored topic as a promising avenue of gerontological research.     

自噬调控衰老的研究进展

随着机体老化,组织器官可发生不可逆退行性改变,这些变化与疾病和死亡密切相关。自噬是细胞内一种重要的分解代谢过程,在维持细胞稳态和促进长寿中起重要作用,机体衰老后,其自噬调节能力也随之下降。本文综述了自噬与衰老相关疾病的关系,明确自噬调控衰老的相关分子机制可能为治疗衰老相关疾病提供新的靶点。     

Recycle or die: the role of autophagy in cardioprotection

Autophagy is a highly conserved cellular process responsible for the degradation of long-lived proteins and organelles. Autophagy occurs at low levels under normal conditions, but is upregulated in response to stress such as nutrient deprivation, hypoxia, mitochondrial dysfunction, and infection. Upregulation of autophagy may be beneficial to the cell by recycling of proteins to generate free amino acids and fatty acids needed to maintain energy production, by removing damaged organelles, and by preventing accumulation of protein aggregates. In contrast, there is evidence that enhanced autophagy can contribute to cell death, possibly through excessive self-digestion. In the heart, autophagy has an essential role for maintaining cellular homeostasis under normal conditions and increased autophagy can be seen in conditions of starvation, ischemia/reperfusion, and heart failure. However, the functional significance of autophagy in heart disease is unclear and controversial. Here, we review the literature and discuss the evidence that autophagy can have both beneficial and detrimental roles in the myocardium depending on the level of autophagy, and discuss potential mechanisms by which autophagy provides protection in cells.     

Skeletal muscle autophagy and apoptosis during aging: Effects of calorie restriction and life-long exercise

Sarcopenia, loss of muscle mass and function, is a common feature of aging. Oxidative damage and apoptosis are likely underlying factors. Autophagy, a process for the degradation of cellular constituents, may be a mechanism to combat cell damage and death. We investigated the effect of age on autophagy and apoptosis in plantaris muscle of male Fischer 344 rats that were either fed ad libitum, or mild, life-long calorie restricted (CR) alone or combined with life-long voluntary exercise. Upstream autophagy-regulatory proteins were either upregulated with age (Beclin-1) or unchanged (Atg7 and 9). LC3 gene and protein expression pattern as well as LAMP-2 gene expression, both downstream regulators of autophagy, however, suggested an age-related decline in autophagic degradation. Atg protein expression and LC3 and LAMP-2 gene expression were improved in CR rats with or without exercise. The age-related increase in oxidative damage and apoptosis were attenuated by the treatments. Both, oxidative damage and apoptosis correlated negatively with autophagy. We conclude that mild CR attenuates the age-related impairment of autophagy in rodent skeletal muscle, which might be one of the mechanisms by which CR attenuates age-related cellular damage and cell death in skeletal muscle in vivo.     

Too much or not enough of a good thing — The Janus faces of autophagy in cardiac fuel and protein homeostasis

Cells respond to changes in their environment and in their intracellular milieu by altering specific pathways of protein synthesis and degradation. Autophagy is a highly conserved catabolic process involved in the degradation of long-lived proteins, damaged organelles, and subcellular structures. The process is orchestrated by the autophagy related protein (Atg) to form the double-membrane structure autophagosomes, which then fuse with lysosomes to generate autophagolysosomes where subcellular contents are degraded for a variety of cellular processes. Alterations in autophagy play an important role in diseases including cancer, neurodegenerative diseases, aging, metabolic diseases, inflammation and cardiovascular diseases. In the latter, dysregulated autophagy is speculated to contribute to the onset and development of atherosclerosis, ischemia/reperfusion injury, cardiomyopathy, diabetes mellitus, and hypertension. Autophagy may be both adaptive and beneficial for cell survival, or maladaptive and detrimental for the cell. Basal autophagy plays an essential role in the maintenance of cellular homeostasis whereas excessive autophagy may lead to autophagic cell death. The point and counterpoint discussion highlights adaptive vs. maladaptive autophagy. In this review, we discuss the molecular control of autophagy, focusing particularly on the regulation of physiologic vs. defective autophagy.     

The role and modulation of autophagy in experimental models of myocardial ischemia-reperfusion injury

A physiological sequence called autophagy qualitatively determines cellular viability by removing protein aggregates and damaged cyto-plasmic constituents, and contributes significantly to the degree of myocardial ischemia-reperfusion （I/R） injury. This tightly orchestrated cata-bolic cellular‘housekeeping’ process provides cells with a new source of energy to adapt to stressful conditions. This process was first described as a pro-survival mechanism, but increasing evidence suggests that it can also lead to the demise of the cell. Autophagy has been implicated in the pathogenesis of multiple cardiac conditions including myocardial I/R injury. However, a debate persists as to whether autophagy acts as a protec-tive mechanism or contributes to the injurious effects of I/R injury in the heart. This controversy may stem from several factors including the va-riability in the experimental models and species, and the methodology used to assess autophagy. This review provides updated knowledge on the modulation and role of autophagy in isolated cardiac cells subjected to I/R, and the growing interest towards manipulating autophagy to increase the survival of cardiac myocytes under conditions of stress-most notably being I/R injury. Perturbation of this evolutionarily conserved intracellular cleansing autophagy mechanism, by targeted modulation through, among others, mammalian target of rapamycin （mTOR） inhibitors, adenosine monophosphate-activated protein kinase （AMPK） modulators, calcium lowering agents, resveratrol, longevinex, sirtuin activators, the proapoptotic gene Bnip3, IP3 and lysosome inhibitors, may confer resistance to heart cells against I/R induced cell death. Thus, therapeutic ma-nipulation of autophagy in the challenged myocardium may benefit post-infarction cardiac healing and remodeling.     

Autophagy in cardiac myocyte homeostasis, aging, and pathology

Autophagy, an intralysosomal degradation of cells' own constituents that includes macro-, micro-, and chaperone-mediated autophagy, plays an important role in the renewal of cardiac myocytes. This cell type is represented by long-lived postmitotic cells with very poor (if any) replacement through differentiation of stem cells. Macroautophagy, the most universal form of autophagy, is responsible for the degradation of various macromolecules and organelles including mitochondria and is activated in response to stress, promoting cell survival. This process is also involved in programmed cell death when injury is irreversible. Even under normal conditions, autophagy is somewhat imperfect, underlying gradual accumulation of defective mitochondria and lipofuscin granules within aging cardiac myocytes. Autophagy is involved in the most important cardiac pathologies including myocardial hypertrophy, cardiomyopathies, and ischemic heart disease, a fact that has led to increasing attention to this process.     

Cellular senescence—an aging hallmark in chronic obstructive pulmonary disease pathogenesis

Chronic obstructive pulmonary disease (COPD),¹ a representative aging-related pulmonary disorder, is mainly caused by cigarette smoke (CS) exposure. Age is one of the most important risk factors for COPD development, and increased cellular senescence in tissues and organs is a component of aging. CS exposure can induce cellular senescence, as characterized by irreversible growth arrest and aberrant cytokine secretion of the senescence-associated secretory phenotype; thus, accumulation of senescent cells is widely implicated in COPD pathogenesis. CS-induced oxidative modifications to cellular components may be causally linked to accelerated cellular senescence, especially during accumulation of damaged macromolecules. Autophagy is a conserved mechanism whereby cytoplasmic components are sent for lysosomal degradation to maintain proteostasis. Autophagy diminishes with age, and loss of proteostasis is one of the hallmarks of aging. We have reported the involvement of insufficient autophagy in regulating CS-induced cellular senescence with respect to COPD pathogenesis. However, the role of autophagy in COPD pathogenesis can vary based on levels of cell stress and type of selective autophagy because excessive activation of autophagy can be responsible for inducing regulated cell death. Senotherapies targeting cellular senescence may be effective COPD treatments. Autophagy activation could be a promising sonotherapeutic approach, but the optimal modality of autophagy activation should be examined in future studies.     

Autophagic programmed cell death by selective catalase degradation

Autophagy plays a central role in regulating important cellular functions such as cell survival during starvation and control of infectious pathogens. Recently, it has been shown that autophagy can induce cells to die; however, the mechanism of the autophagic cell death program is unclear. We now show that caspase inhibition leading to cell death by means of autophagy involves reactive oxygen species (ROS) accumulation, membrane lipid oxidation, and loss of plasma membrane integrity. Inhibition of autophagy by chemical compounds or knocking down the expression of key autophagy proteins such as ATG7, ATG8, and receptor interacting protein (RIP) blocks ROS accumulation and cell death. The cause of abnormal ROS accumulation is the selective autophagic degradation of the major enzymatic ROS scavenger, catalase. Caspase inhibition directly induces catalase degradation and ROS accumulation, which can be blocked by autophagy inhibitors. These findings unveil a molecular mechanism for the role of autophagy in cell death and provide insight into the complex relationship between ROS and nonapoptotic programmed cell death.     

Cardiomyocyte autophagy: Remodeling, repairing, and reconstructing the heart

Autophagy is an evolutionarily conserved catabolic pathway of lysosome-dependent turnover of damaged proteins and organelles. When nutrients are in short supply, bulk removal of cytoplasmic components by autophagy replenishes depleted energy stores, a process critical for maintaining cellular homeostasis. However, prolonged activation of autophagic pathways can result in cell death. Longstanding evidence has linked the stimulation of lysosomal pathways to pathologic cardiac remodeling and a number of cardiac diseases, including heart failure and ischemia. Only recently, however, has work begun to parse cytoprotective autophagy from autophagy that contributes to disease pathogenesis. Current thinking suggests that the effects of autophagy exist on a continuum, with the eliciting triggers, the duration and amplitude of autophagic flux, and possibly the targeted intra cellular cargo as critical determinants of the end result. Deciphering how autophagy participates in basal homeostasis of the heart, in aging, and in disease pathogenesis may uncover novel insights with clinical relevance in the treatment of heart disease.     

Autophagy in the myocardium: Dying for survival?

Autophagy is an intracellular phenomenon in which a cell digests its own constituents. Autophagy is well conserved in nature from lower eukaryotes to mammals and has been attributed to disparate physiological events - including cell death, the mechanism of which is different from apoptosis. However, unlike in apoptosis, in which a family of cysteine proteases (caspases) and a number of other regulatory proteins have been identified and characterized, the mechanism of autophagic cell death remains unclear. In addition, the general mechanisms by which autophagy is initiated and modulated are just emerging, and several lines of evidence indicate that activated class I phosphatidylinositol 3-kinase and mammalian target of rapamycin (mTOR) inhibit autophagy, while class III phosphatidylinositol 3-kinase acts as a facilitator. Autophagy has been attributed to a number of cardiac disorders, such as ischemic cardiomyopathy, cardiac hypertrophy, hemochromatosis and myocardial aging. Induction of ventricular hypertrophy is associated with decreased autophagy, whereas it is enhanced during the regression of hypertrophy. Induction of acute cardiotoxicity by the anticancer drug anthracycline is also associated with massive cardiomyocyte loss due to autophagy (and apoptosis). Myocyte loss due to autophagy has also been reported during progression from compensated hypertrophy to heart failure in a pressure-overloaded model. Although the depth and dimension of the regulatory network that modulates autophagy in mammalian cells has yet to emerge, existing evidence suggests that it is an integral part of maintaining cellular metabolism, organelle homeostasis and redox equilibrium. Thus, it is a likely possibility that autophagy plays a crucial role in maintaining healthy myocytes in the myocardium.     

FADD and caspase-8 control the outcome of autophagic signaling in proliferating T cells

Fas-associated death domain protein (FADD) and caspase-8 (casp8) are vital intermediaries in apoptotic signaling induced by tumor necrosis factor family ligands. Paradoxically, lymphocytes lacking FADD or casp8 fail to undergo normal clonal expansion following antigen receptor cross-linking and succumb to caspase-independent cell death upon activation. Here we show that T cells lacking FADD or casp8 activity are subject to hyperactive autophagic signaling and subvert a cellular survival mechanism into a potent death process. T cell autophagy, enhanced by mitogenic signaling, recruits casp8 through interaction with FADD:Atg5-Atg12 complexes. Inhibition of autophagic signaling with 3-methyladenine, dominant-negative Vps34, or Atg7 shRNA rescued T cells expressing a dominant-negative FADD protein. The necroptosis inhibitor Nec-1, which blocks receptor interacting protein kinase 1 (RIP kinase 1), also completely rescued T cells lacking FADD or casp8 activity. Thus, while autophagy is necessary for rapid T cell proliferation, our findings suggest that FADD and casp8 form a feedback loop to limit autophagy and prevent this salvage pathway from inducing RIPK1-dependent necroptotic cell death. Thus, linkage of FADD and casp8 to autophagic signaling intermediates is essential for rapid T cell clonal expansion and may normally serve to promote caspase-dependent apoptosis under hyperautophagic conditions, thereby averting necrosis and inflammation in vivo.     

Role of autophagy in histone deacetylase inhibitor-induced apoptotic and nonapoptotic cell death

Autophagy is a cellular catabolic pathway by which long-lived proteins and damaged organelles are targeted for degradation. Activation of autophagy enhances cellular tolerance to various stresses. Recent studies indicate that a class of anticancer agents, histone deacetylase (HDAC) inhibitors, can induce autophagy. One of the HDAC inhibitors, suberoylanilide hydroxamic acid (SAHA), is currently being used for treating cutaneous T-cell lymphoma and under clinical trials for multiple other cancer types, including glioblastoma. Here, we show that SAHA increases the expression of the autophagic factor LC3, and inhibits the nutrient-sensing kinase mammalian target of rapamycin (mTOR). The inactivation of mTOR results in the dephosphorylation, and thus activation, of the autophagic protein kinase ULK1, which is essential for autophagy activation during SAHA treatment. Furthermore, we show that the inhibition of autophagy by RNAi in glioblastoma cells results in an increase in SAHA-induced apoptosis. Importantly, when apoptosis is pharmacologically blocked, SAHA-induced nonapoptotic cell death can also be potentiated by autophagy inhibition. Overall, our findings indicate that SAHA activates autophagy via inhibiting mTOR and up-regulating LC3 expression; autophagy functions as a prosurvival mechanism to mitigate SAHA-induced apoptotic and nonapoptotic cell death, suggesting that targeting autophagy might improve the therapeutic effects of SAHA.     

Molecular machinery of autophagy and its implication in cancer

Autophagy is an intracellular lysosome-dependent catabolic process that is indispensable for maintaining cellular homeostasis through the turnover and elimination of defective or redundant proteins and damaged or aged organelles. Recent studies suggest that autophagy may be closely associated with tumorigenesis and the response of tumor cells to chemotherapeutic drugs. This article reviews recent advances in understanding the molecular mechanisms underlying the regulation of autophagy and the role of autophagy in oncogenesis and anticancer therapy. It is paradoxical that autophagy acts as a mechanism for tumor suppression and contributes to the survival of tumors. In addition, whether autophagy in response to chemotherapies results in cell death or instead protects cancer cells from death is complicated, depending on the nature of the cancer and the drug.     

Senescence, apoptosis or autophagy? When a damaged cell must decide its path--a mini-review

Many features of aging result from the incapacity of cells to adapt to stress conditions. When damage accumulates irreversibly, mitotic cells from renewable tissues rely on either of two mechanisms to avoid replication. They can permanently arrest the cell cycle (cellular senescence) or trigger cell death programs. Apoptosis (self-killing) is the best-described form of programmed cell death, but autophagy (self-eating), which is a lysosomal degradation pathway essential for homeostasis, reportedly contributes to cell death as well. Unlike mitotic cells, postmitotic cells like neurons or cardiomyocytes cannot become senescent since they are already terminally differentiated. The fate of these cells entirely depends on their ability to cope with stress. Autophagy then operates as a major homeostatic mechanism to eliminate damaged organelles, long-lived or aberrant proteins and superfluous portions of the cytoplasm. In this mini-review, we briefly summarize the molecular networks that allow damaged cells either to adapt to stress or to engage in programmed-cell-death pathways.