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At least 307 records · Page 17Linked to original sources
PubMed2004

Role of mitochondrial permeability transition pores in mitochondrial autophagy.

During autophagy, cells rid themselves of damaged and superfluous mitochondria, as well as other organelles. This activation of mitochondrial turnover could be the result of changes in the physiological state of mitochondria. Confocal microscopy and fluorescence techniques indicate that onset of mitochondrial permeability transition is one such change. The mitochondrial permeability transition is a reversible phenomenon whereby the mitochondrial inner membrane becomes freely permeable to solutes of less than 1500 Da. At onset of the mitochondrial permeability transition, mitochondria depolarize, uncouple, and undergo large amplitude swelling due to opening of permeability transition pores, which may form by aggregation of damaged, misfolded membrane proteins. When injurious cellular stresses occur, cells may protect themselves using autophagy to remove damaged mitochondria and mutated mitochondrial DNA. Ca(2+) overloading, reactive oxygen and nitrogen species, decreased mitochondrial membrane potential, and oxidation of pyridine nucleotides and glutathione all promote mitochondrial damage and onset of the mitochondrial permeability transition. The mitochondrial permeability transition is also associated with necrosis and apoptosis after a variety of stimuli. This review emphasizes the role of the mitochondrial permeability transition as a key event in mitochondrial autophagy.

Aging↗
PubMed2004

Death by design: apoptosis, necrosis and autophagy.

Apoptosis is the principal mechanism by which cells are physiologically eliminated in metazoan organisms. During apoptotic death, cells are neatly carved up by caspases and packaged into apoptotic bodies as a mechanism to avoid immune activation. Recently, necrosis, once thought of as simply a passive, unorganized way to die, has emerged as an alternate form of programmed cell death whose activation might have important biological consequences, including the induction of an inflammatory response. Autophagy has also been suggested as a possible mechanism for non-apoptotic death despite evidence from many species that autophagy represents a survival strategy in times of stress. Recent advances have helped to define the function of and mechanism for programmed necrosis and the role of autophagy in cell survival and suicide.

Animals↗
PubMed2005

Growth factor regulation of autophagy and cell survival in the absence of apoptosis.

In animals, cells are dependent on extracellular signals to prevent apoptosis. However, using growth factor-dependent cells from Bax/Bak-deficient mice, we demonstrate that apoptosis is not essential to limit cell autonomous survival. Following growth factor withdrawal, Bax-/-Bak-/- cells activate autophagy, undergo progressive atrophy, and ultimately succumb to death. These effects result from loss of the ability to take up sufficient nutrients to maintain cellular bioenergetics. Despite abundant extracellular nutrients, growth factor-deprived cells maintain ATP production from catabolism of intracellular substrates through autophagy. Autophagy is essential for maintaining cell survival following growth factor withdrawal and can sustain viability for several weeks. During this time, cells respond to growth factor readdition by rapid restoration of the ability to take up and metabolize glucose and by subsequent recovery of their original size and proliferative potential. Thus, growth factor signal transduction is required to direct the utilization of sufficient exogenous nutrients to maintain cell viability.

Animals↗
PubMed2005

Eating oneself and uninvited guests: autophagy-related pathways in cellular defense.

The eukaryotic cell uses an evolutionarily conserved lysosomal pathway of self-digestion (autophagy) for survival when extracellular nutrients are limited. In this issue of Cell, new evidence indicates that autophagy is used to for survival when intracellular nutrients are limited by growth factor deprivation (Lum et al., 2005). Other recent studies indicate that the autophagy machinery is also used to degrade foreign microbial invaders (xenophagy).

Animals↗
PubMed2006

Autophagy in MHC class II antigen processing.

Durable adaptive immunity is dependent upon CD4 T-cell recognition of MHC class II molecules that display peptides from exogenous and endogenous antigens. Endogenously expressed cytosolic and nuclear antigens access MHC class II by way of several intracellular autophagic routes. These pathways include macroautophagy, microautophagy and chaperone-mediated autophagy. Macroautophagy can deliver antigens into autophagosomes for processing by acidic proteases before MHC class II presentation. However, other endogenous antigens are processed by cytoplasmic proteases, yielding fragments that translocate via chaperone-mediated autophagy into the endosomal network to intersect MHC class II. Cross-talk between autophagy pathways, particularly in response to stress, appears to balance the relative efficiency of each pathway. This might limit redundancy, giving MHC class II broader access to antigens within intracellular compartments distinct from the endosomal network.

Animals↗
PubMed2005

Autophagy in innate and adaptive immunity.

Recently, several groups made a nearly simultaneous discovery that autophagic degradation represents a previously unrecognized effector of innate and adaptive immunity. Despite the fact that hints to these phenomena hail back to earlier sporadic reports, autophagy has, until now, received attention primarily as a fundamental cellular homeostasis pathway, whereby cytoplasm portions get sequestered by the membrane for delivery to lysosomes. This process leads to the removal of damaged or surplus organelles and digests stable, long-lived macromolecules. Autophagy has been implicated previously in both health-promoting and disease-associated states, in cancer, neurodegeneration, development and aging. A protective role has recently been demonstrated in infectious diseases, which represents a previously unrecognized immune mechanism acting against intracellular microbes. This review reviews autophagy as an immune mechanism.

Animals↗
PubMed2006

Signalling and autophagy regulation in health, aging and disease.

It has become clear in recent years that autophagy not only serves to produce amino acids for ongoing protein synthesis and to produce substrates for energy production when cells become starved but autophagy is also able to eliminate defective cell structures and for this reason the process may be implicated in several diseased states. Autophagy is controlled by complex signalling pathways, including that used by insulin. In these pathways, phosphatidylinositol 3-kinases and the protein kinase mTOR play important roles.

Aging↗
PubMedDate not supplied

Diet restriction induced autophagy: a lysosomal protective system against oxidative- and pollutant-stress and cell injury.

Nutrient deprivation or dietary restriction (DR) confers protection against ageing and stress in many animals and induced lysosomal autophagy is part of this mechanism. The effects of dietary restriction on the toxicity of copper and the polycyclic aromatic hydrocarbon phenanthrene have been investigated in the common marine mussel Mytilus edulis. The findings show that DR-induced autophagy facilitates the recovery of the digestive gland (i.e., molluscan liver analogue) from cell injury caused by both copper and phenanthrene. It is inferred that DR-induced autophagy and lysosomal proteolysis results in improved cellular "housekeeping" through the more efficient removal of oxidatively and pollutant damaged proteins (e.g., protein carbonyls, protein adducts, etc.) and that this contributes to stress resistance.

Animals↗
PubMed2006

Glycogen autophagy in glucose homeostasis.

Glycogen autophagy, the sequestration and degradation of cell glycogen in the autophagic vacuoles, is a selective, hormonally controlled and highly regulated process, representing a mechanism of glucose homeostasis under conditions of demand for the production of this sugar. In the newborn animals, this process is induced by glucagon secreted during the postnatal hypoglycemia and inhibited by insulin and parenteral glucose, which abolishes glucagon secretion. Hormonal action is mediated by the cAMP/protein kinase A (induction) and phosphoinositides/mTOR (inhibition) pathways that converge on common targets, such as the protein phosphatase 2A to regulate autophgosomal glycogen-hydrolyzing acid glucosidase and glycogen autophagy. Intralysosomal phosphate exchange reactions, which are affected by changes in the calcium levels and acid mannose 6- and acid glucose 6-phosphatase activities, can modify the intralysosomal composition in phosphorylated and nonphosphorylated glucose and promote the exit of free glucose through the lysosomal membrane. Glycogen autophagy-derived nonphosphorylated glucose assists the hyaloplasmic glycogen degradation-derived glucose 6-phosphate to combat postnatal hypoglycemia and participates in other metabolic pathways to secure the fine tuning of glucose homeostasis during the neonatal period.

Animals↗
PubMed1987

Short-term stimulation by propranolol and verapamil of cardiac cellular autophagy.

The influence of propranolol and verapamil, i.e. two cardiodepressant drugs differing in their pharmacological actions, on cellular autophagy in the left ventricular myocardium of the rat was investigated. In the first experimental series 10 animals were given propranolol subcutaneously (3 mg/kg body weight). Ten controls received physiological saline. In the second series 8 animals were treated with verapamil subcutaneously (9 mg/kg body weight) and 8 controls with physiological saline. Two to 4 h after the injections in the first series and 1 3/4 to 3 h in the second series retrograde perfusion fixation was carried out via the abdominal aorta with a paraformaldehyde-glutaraldehyde mixture. Myocardial tissue from the left anterior wall was processed for electron microscopy and was morphometrically evaluated for volume fraction and numerical density of early stages of autophagic vacuoles (AVs). Propranolol and verapamil significantly increased the AV volume fraction 4.3- and 2.7-fold, respectively. The numerical density was increased by the two drugs, although to a lesser degree (2.3-fold, and 1.7-fold, respectively). As verapamil affects neither the beta-adrenoreceptors nor the intracellular levels of the second messenger cAMP, the only common denominator for the stimulation of cellular autophagy seems to be the cardiodepressive effect of the two drugs. The data suggest that the rise in cellular autophagy is an early regulatory step in the adaptation of heart muscle mass to reduced work load.

Animals↗
PubMed2002

A novel protein complex linking the delta 2 glutamate receptor and autophagy: implications for neurodegeneration in lurcher mice.

Autophagy is a pathway for bulk degradation of subcellular constituents that is hyperactivated in many neurodegenerative conditions. It has been considered a second form of programmed cell death. Death of cerebellar Purkinje cells in lurcher animals is due to a mutation in GluRdelta2 that results in its constitutive activation. Here we have identified protein interactions between GluRdelta2, a novel isoform of a PDZ domain-containing protein (nPIST) that binds to this receptor, and Beclin1. nPIST and Beclin1 can synergize to induce autophagy. GluRdelta2(Lc), but not GluRdelta2(wt), can also induce autophagy. Furthermore, dying lurcher Purkinje cells contain morphological hallmarks of autophagic death in vivo. These results provide strong evidence that a direct link exists between GluRdelta2(Lc) receptor and stimulation of the autophagic pathway in dying lurcher Purkinje cells.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease.

Huntington disease is one of nine inherited neurodegenerative disorders caused by a polyglutamine tract expansion. Expanded polyglutamine proteins accumulate abnormally in intracellular aggregates. Here we show that mammalian target of rapamycin (mTOR) is sequestered in polyglutamine aggregates in cell models, transgenic mice and human brains. Sequestration of mTOR impairs its kinase activity and induces autophagy, a key clearance pathway for mutant huntingtin fragments. This protects against polyglutamine toxicity, as the specific mTOR inhibitor rapamycin attenuates huntingtin accumulation and cell death in cell models of Huntington disease, and inhibition of autophagy has the converse effects. Furthermore, rapamycin protects against neurodegeneration in a fly model of Huntington disease, and the rapamycin analog CCI-779 improved performance on four different behavioral tasks and decreased aggregate formation in a mouse model of Huntington disease. Our data provide proof-of-principle for the potential of inducing autophagy to treat Huntington disease.

Animals↗
PubMed2005

Autophagy in metazoans: cell survival in the land of plenty.

Cells require a constant supply of macromolecular precursors and oxidizable substrates to maintain viability. Unicellular eukaryotes lack the ability to regulate nutrient concentrations in their extracellular environment. So when environmental nutrients are depleted, these organisms catabolize existing cytoplasmic components to support ATP production to maintain survival, a process known as autophagy. By contrast, the environment of metazoans normally contains abundant extracellular nutrients, but a cell's ability to take up these nutrients is controlled by growth factor signal transduction. Despite evolving the ability to maintain a constant supply of extracellular nutrients, metazoans have retained a complete set of autophagy genes. The physiological relevance of autophagy in such species is just beginning to be explored.

Animals↗
PubMed2026

Enoxaparin induces apoptosis and autophagy, modulates inflammatory signaling, and reduces oxidative DNA damage in breast and liver cancer cells.

Cancer progression involves intricate interactions between inflammatory signaling, programmed cell death mechanisms, and oxidative stress. Although enoxaparin is widely used for managing cancer-associated thrombosis, its direct cellular effects on tumor biology remain insufficiently characterized. This study aimed to evaluate the impact of enoxaparin on apoptosis, autophagy, inflammatory mediators, and oxidative DNA damage in breast (MDA-MB-231) and liver (HepG2) cancer cell lines. MDA-MB-231, HepG2, and non-cancerous HEK-293 cells were treated with varying concentrations (5, 10, 20, 40, and 80 mg/mL) of enoxaparin for 24 and 48 h. Cell viability was assessed using the MTT assay, while apoptosis was quantified by TUNEL analysis. Immunofluorescence staining was employed to evaluate the expression of NF-κB, IL-6, TNF-α, LC3, and p62. Oxidative DNA damage was determined by measuring extracellular 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels using a competitive ELISA. Statistical analyses were conducted to compare the treated and control groups. Enoxaparin significantly reduced cell viability in MDA-MB-231 and HepG2 cells without inducing cytotoxicity in HEK-293 cells. Apoptosis was markedly increased in both cancer cell lines following treatment. Enoxaparin differentially modulated inflammatory signaling; NF-κB expression was significantly increased in MDA-MB-231 cells, accompanied by suppression of IL-6 and TNF-α, whereas no significant inflammatory changes were observed in HepG2 cells. Enoxaparin treatment was observed to increase LC3 and p62 expression in both MDA-MB-231 and HepG2 cells, triggering autophagy-related pathways. Moreover, enoxaparin significantly reduced extracellular 8-OHdG levels, suggesting a reduction in oxidative DNA damage. Enoxaparin exhibits multifaceted anticancer effects by promoting apoptosis and autophagy, selectively modulating inflammatory pathways, and reducing oxidative DNA damage in breast and liver cancer cells.

Humans↗
PubMed2000

Bcl-2 down-regulation causes autophagy in a caspase-independent manner in human leukemic HL60 cells.

To understand the roles of bcl-2 for the survival of leukemic cells, we constructed human leukemic HL60 transformant lines in which full length bcl-2 antisense message was conditionally expressed by a tetracycline-regulatable expression system. Cell growth was completely inhibited after antisense message induction and massive cell death was induced. Electron microscopic examinations show that cells died by autophagy, but not by apoptosis. The morphology and the function of mitochondria remained intact: neither the reduction in mitochondrial membrane potential nor the nuclear translocation of AIF, a mitochondrial protein that translocates to nuclei in cases of apoptosis, was observed. Caspase inhibitors did not rescue bcl-2-antisense-mediated autophagy. Thus, bcl-2 is essential for leukemic cell survival and its down-regulation results in autophagy. Cell Death and Differentiation (2000) 7, 1263 - 1269.

Anti-Bacterial Agents↗
PubMed2005

Autophagy: molecular machinery for self-eating.

Autophagy is a highly conserved process in eukaryotes in which the cytoplasm, including excess or aberrant organelles, is sequestered into double-membrane vesicles and delivered to the degradative organelle, the lysosome/vacuole, for breakdown and eventual recycling of the resulting macromolecules. This process has an important role in various biological events such as adaptation to changing environmental conditions, cellular remodeling during development and differentiation, and determination of lifespan. Auto-phagy is also involved in preventing certain types of disease, although it may contribute to some pathologies. Recent studies have identified many components that are required to drive this complicated cellular process. Auto-phagy-related genes were first identified in yeast, but homologs are found in all eukaryotes. Analyses in a range of model systems have provided huge advances toward understanding the molecular basis of autophagy. Here we review our current knowledge on the machinery and molecular mechanism of autophagy.

Animals↗
PubMed2006

A novel cell type-specific role of p38alpha in the control of autophagy and cell death in colorectal cancer cells.

Cancer develops when molecular pathways that control the fine balance between proliferation, differentiation, autophagy and cell death undergo genetic deregulation. The prospects for further substantial advances in the management of colorectal cancer reside in a systematic genetic and functional dissection of these pathways in tumor cells. In an effort to evaluate the impact of p38 signaling on colorectal cancer cell fate, we treated HT29, Caco2, Hct116, LS174T and SW480 cell lines with the inhibitor SB202190 specific for p38alpha/beta kinases. We report that p38alpha is required for colorectal cancer cell homeostasis as the inhibition of its kinase function by pharmacological blockade or genetic inactivation causes cell cycle arrest, autophagy and cell death in a cell type-specific manner. Deficiency of p38alpha activity induces a tissue-restricted upregulation of the GABARAP gene, an essential component of autophagic vacuoles and autophagosomes, whereas simultaneous inhibition of autophagy significantly increases cell death by triggering apoptosis. These data identify p38alpha as a central mediator of colorectal cancer cell homeostasis and establish a rationale for the evaluation of the pharmacological manipulation of the p38alpha pathway in the treatment of colorectal cancer.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Ras is involved in the negative control of autophagy through the class I PI3-kinase.

Ras proteins exert a pivotal regulatory function in signal transduction involved in cell proliferation and their activation mutation leads to malignant cell transformation. However, the role of Ras proteins in autophagy, an intracellular protein degradation process in cell growth control is unknown. In the present study, we demonstrate that the degradation of long-lived proteins in NIH3T3 cells in response to nutrient starvation was significantly suppressed by oncogenic RasVal12 transformation in a rapamycin (mTOR inhibitor)-sensitive manner. Morphologic observations also show the decrease in the formation of autophagic vacuoles upon the Ras transformation. Furthermore, epidermal growth factor or serum downregulated the protein degradation induced by serum starvation and the dominant-negative RasAsn17 mutant counteracted this suppressive effect, indicating that Ras mediates the growth factor downregulation of autophagy. The suppression of protein degradation by the activated RasVal12 was mediated by the class I phosphatidyl inositol 3-kinase (PI3-kinase), but not either or Raf Ral GDS. Consistent with this, RasVal12 and class I PI3-kinase inhibited the rate of autophagic sequestration of LDH. These data suggest that Ras plays a critical role as a negative regulator for nutrient deprivation-induced autophagy through the class I PI3-kinase signaling pathway.

Animals↗