Acid Vesicles

Author: Gianpiero Pescarmona
Date: 27/03/2009


Autophagy, or autophagocytosis, is a catabolic process involving the degradation of a cell's own components through the lysosomal machinery.
It is the major mechanism by which a starving cell reallocates nutrients from unnecessary processes to more-essential processes or from damaged to healthy parts of the cell (competition).
The same mechanism is used against pathogenes (bacteria and virus), other suffering cells, misfolded or no longer useful proteins, extracellular proteins like serum or extracellular matrix proteins, all used as nutriens.
MHC I is involved in the recognition of proteins to be digested. ??????
It is an active process strongly dependent on the cell capability to acidify lysosomes.

Wikigenes Autophagy

Steps details


ATG1/Ulk1 is dowsntream of mTOR and is involved in autophagy induction.

mTOR patway is down-regulated by AMPK (activated by AMP, Metformin, AICAR)

AMPK activation depends on:

  • AMP
  • Metformin
    • purine biosynthesis
    • histidine catabolism

NUCLEATION Autophagosome nucleation is driven by phosphatidylinositol (PI) phosphorylation.

  • the process is mediated by a lipid kinase signaling complex: Beclin 1, Vps15, Vps34 (Ambra1 favors Vps34/Beclin 1 interaction)
  • UVRAG and Bif-1 have been described as additional Beclin 1 complex regulators.
  • Beclin 1 proautophagic roles are inhibited by its binding to Bcl2 and/or Bcl-XL, which act in the crosstalk between autophagy and apoptosis.

  • APOPTOSIS Bcl2-like pro-apoptotic and antiapoptotic proteins regulate cytochrome c release from mitochondria. Cytosolic cytochrome c binds Apaf1 and induces the recruitment of the initiator caspase 9 (Casp9) on the active apoptosome. The active apoptosome, in turn, activates caspase 3 (Casp3), which mediates cell destruction.

Autophagy at Kegg Pathways

Atg5: more than an autophagy factor 2006

Papers lysosomal parkinson's schneider's+schneider

Systems biology of the autophagy-lysosomal pathway. 2011 Autophagy. 2011 May 1;7(5).

  • The mechanisms of the control and activity of the autophagy-lysosomal protein degradation machinery is emerging as an important theme for neurodevelopment and neurodegeneration. However, the underlying regulatory and functional networks of known genes controlling autophagy and lysosomal function and their role in disease are relatively unexplored. We performed a systems biology-based integrative computational analysis to study the interactions between molecular components and to develop models for regulation and function of genes involved in autophagy and lysosomal function. Specifically, we analyzed transcriptional and microRNA-based posttranscriptional regulation of these genes and performed functional enrichment analyses to understand their involvement in nervous system-related diseases and phenotypes. Transcriptional regulatory network analysis showed that binding sites for transcription factors, SREBP1, USF, AP-1 and NFE2, are common among autophagy and lysosomal genes. MicroRNA enrichment analysis revealed miR-130, 98, 124, 204 and 142 as the putative posttranscriptional regulators of the autophagy-lysosomal pathway genes. Pathway enrichment analyses revealed that the mTOR and insulin signaling pathways are important in the regulation of genes involved in autophagy. In addition, we found that glycosaminoglycan and glycosphingolipid pathways also make a major contribution to lysosomal gene regulation. The analysis confirmed the known contribution of the autophagy-lysosomal genes to Alzheimer and Parkinson diseases and also revealed potential involvement in tuberous sclerosis, neuronal ceroid-lipofuscinoses, sepsis, and lung, liver and prostatic neoplasms. To further probe the impact of autophagy-lysosomal gene deficits on neurologically-linked phenotypes, we also mined the mouse knockout phenotype data for the autophagy-lysosomal genes and found them to be highly predictive of nervous system dysfunction. Overall this study demonstrates the utility of systems biology-based approaches for understanding the autophagy-lysosomal pathways and gaining additional insights into the potential impact of defects in these complex biological processes.

Self-eating and self-killing: crosstalk between autophagy and apoptosis 2007
ATG7 or ATG5

1. FUNCTION: Functions as an E1 enzyme essential for multisubstrates such as GABARAPL1 and ATG12. Forms intermediate conjugates with GABARAPL1 (GABARAPL2, GABARAP or MAP1ALC3). Formation of the final GABARAPL1-PE conjugate is essential for autophagy (By similarity).
2. SUBUNIT: Homodimer (By similarity). Interacts with ATG3 and ATG12. The complex, composed of ATG3 and ATG7, plays a role in the conjugation of ATG12 to ATG5.
3. SUBCELLULAR LOCATION: Cytoplasm (Probable).
4. ALTERNATIVE PRODUCTS: Event=Alternative splicing; Named isoforms=2; Name=1; IsoId=O95352-1; Sequence=Displayed; Name=2; IsoId=O95352-2; Sequence=VSP_013205;
5. TISSUE SPECIFICITY: Widely expressed, especially in kidney, liver, lymph nodes and bone marrow.
6. DOMAIN: The C-terminal part of the protein is essential for the dimerization and interaction with ATG3 and ATG12 (By similarity).
7. SIMILARITY: Belongs to the ATG7 family.

Gaba R increases Cl- influx. What about CFTR?

2009-10-06T13:59:15 - Gianpiero Pescarmona


Diabetologia. 2009 Jun;52(6):1083-6. Epub 2009 Apr 15.Click here to read Links

Autophagy in human type 2 diabetes pancreatic beta cells. 2009
Masini M, Bugliani M, Lupi R, del Guerra S, Boggi U, Filipponi F, Marselli L, Masiello P, Marchetti P.

Department of Experimental Pathology, University of Pisa, Pisa, Italy.

AIMS/HYPOTHESIS: Beta cell loss contributes to type 2 diabetes, with increased apoptosis representing an underlying mechanism. Autophagy, i.e. the physiological degradation of damaged organelles and proteins, may, if altered, be associated with a distinct form of cell death. We studied several features of autophagy in beta cells from type 2 diabetic patients and assessed the role of metabolic perturbation and pharmacological intervention. METHODS: Pancreatic samples were obtained from organ donors and isolated islets prepared both by collagenase digestion and density gradient centrifugation. Beta cell morphology and morphometry were studied by electron microscopy. Gene expression studies were performed by quantitative RT-PCR. RESULTS: Using electron microscopy, we observed more dead beta cells in diabetic (2.24 +/- 0.53%) than control (0.66 +/- 0.52%) samples (p < 0.01). Massive vacuole overload (suggesting altered autophagy) was associated with 1.18 +/- 0.54% dead beta cells in type 2 diabetic samples and with 0.36 +/- 0.26% in control samples (p < 0.05). Density volume of autophagic vacuoles and autophagosomes was significantly higher in diabetic beta cells. Unchanged gene expression of beclin-1 and ATG1 (also known as ULK1), and reduced transcription of LAMP2 and cathepsin B and D was observed in type 2 diabetic islets. Exposure of non-diabetic islets to increased NEFA concentration led to a marked increase of vacuole accumulation, together with enhanced beta cell death, which was associated with decreased LAMP2 expression. Metformin ameliorated autophagy alterations in diabetic beta cells and beta cells exposed to NEFA, a process associated with normalisation of LAMP2 expression. CONCLUSIONS/INTERPRETATION: Beta cells in human type 2 diabetes have signs of altered autophagy, which may contribute to loss of beta cell mass. To preserve beta cell mass in diabetic patients, it may be necessary to target multiple cell-death pathways.

2009-10-06T09:43:15 - Gianpiero Pescarmona

Autophagy inducers

Autophagy, lithium, and amyotrophic lateral sclerosis.
PMID: 19609902 Related Articles
Authors: Pasquali, L, Longone, P, Isidoro, C, Ruggieri, S, Paparelli, A, Fornai, F
Journal: Muscle Nerve, Vol. 40 (2): 173-94, 2009
Abstract: In this article we provide an overview of the intersection between amyotrophic lateral sclerosis (ALS) and the autophagy pathway and discuss the potential protective effects of lithium through mechanisms that recruit autophagy and other effects. The autophagy pathway is recruited during motor neuron (MN) death both in vitro and in vivo. Despite a few controversial issues concerning the significance (detrimental/protective) of autophagy in ALS, recent findings indicate a protective role. Lithium in low doses is a well-known autophagy inducer that clears misfolded proteins and altered mitochondria from MNs. Moreover, lithium preserves mitochondria and sustains their genesis. This effect is replicated by rapamycin , which is an autophagy inducer but with a different mechanism from lithium. Lithium also increases the number of Renshaw cells that are affected early during the progression of experimental ALS. Again, lithium has been reported to decrease glial proliferation in the ALS spinal cord and induces sprouting in corticospinal fibers. Muscle Nerve 40: 173-194, 2009.

Tryptamine induces cell death with ultrastructural features of autophagy in neurons and glia: Possible relevance for neurodegenerative disorders. 2006

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