API

Event: 898

Key Event Title

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Disruption, Lysosome

Short name

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Disruption, Lysosome

Key Event Component

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Process Object Action
organelle disassembly lysosome occurrence

Key Event Overview


AOPs Including This Key Event

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Stressors

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Level of Biological Organization

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Biological Organization
Cellular

Cell term

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Cell term
eukaryotic cell


Organ term

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Taxonomic Applicability

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Term Scientific Term Evidence Link
human Homo sapiens Strong NCBI
mouse Mus musculus Strong NCBI

Life Stages

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Sex Applicability

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How This Key Event Works

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Lysosomes were first described by de Duve and colleagues in 1955 [1]. They are acidic, single-membrane bound organelles that are present in all eukaryotic cells and are filled with more than 50 acid hydrolases to serve their purpose of degrading macromolecules [2].

Lysosomes are the terminal organelle of the endocytic pathway, but are also involved in membrane repair and other cellular processes, such as immune responses [3]. The amount of lysosomal enzymes that are released into the cytosol regulates the cell death pathway which is initiated by lysosomal damage: it plays a vital role in the induction of apoptosis, whereas massive lysosomal rupture leads to necrosis [4] [5]. Lysosomes are known to be involved in external as well as internal apoptotic pathways. The external pathway triggers lysosomal destabilization by hydroxyl radicals, p53, caspase 8,through activation of Bax or by ceramide which is converted into sphingosine [6]. The internal apoptotic pathway on the contrary is activated through mitochondrial damage, for example via activation of Bax or Bid, phospholipases, or lysosomal enzymes [6].

The lysosome contains redox-active labile irons which are suggested to be involved in local ROS production via a Fenton-type reaction [7]. It has been shown that lysosomal membrane disruption induced by lysosomotropic detergents causes early induction of lysosomal cathepsin B and D and induction of ferritin, together with an increase of cellular ROS and concomitant reduction of the antioxidants MnSOD (manganese superoxide dismutase) and GSH (glutathione), possibly due to the release of free iron into the cytosol [8] [9]. Released enzymes such as phospholipases can further damage the outer membrane of the mitochondrion, leading to a further increased and uncontrolled ROS production, the release of cytochrome c, the activation of the caspase cascade, and subsequent apoptotic cell death [10].

Considering nanomaterials (NMs) as a trigger for lysosomal damage, recent studies underpinned the importance of lysosomal NM uptake for NM-induced toxicity. Once the material is taken up by a cell and transported to the lysosome by autophagy, the acidic milieu herein can either enhance solubility of a NM, or the material remains in its initial nano form. Both situations can induce toxicity, causing lysosomal swelling, followed by lysosomal disruption and the release of pro-apoptotic proteins [11] [12] [13].


How It Is Measured or Detected

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Lysosomes are typically analysed microscopically.

Changes in morphology can be observed by using acridine orange (AO), a weak base that accumulates in the acidic compartment of the cell mainly composed of lysosomes. Red fluorescence is exhibited when it is highly concentrated in acidic vesicles, while green fluorescence is exhibited when it's less concentrated in other parts of the cell [14] [15] [16].

Lysotracker green (200 nM) is regularly used to assess lysosomal acidification; Anguissola and colleagues reported that it was excited through a 475+/240 nm band pass filter and fluorescence emission was collected through a 515+/220 nm band pass filter. Analysis is performed using microscopical methods such as High Content Analysis [17]. This method as well as use of LysoSensor probes has been reported repeatedly elsewhere, for example [9] [16].

More specific staining can be achieved by staining with antibodies against lysosomal membrane proteins [16].

Lysosomal membrane permeabilization can be visualized by immunostaining of lysosomal enzymes such as cathepsin B [18].


Evidence Supporting Taxonomic Applicability

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Typically, human or murine cell lines are used to assess this event. Examples are

[14]: murine

[15]: murine, human

[19]: murine, human

[10]: human

[17]: human, murine

[9]: human


Evidence for Perturbation by Stressor


Overview for Molecular Initiating Event

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References

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  1. de Duve C, Pressman BC, Gianetto R, Wattiaux R, Applemans F. Tissue fractionation studies. 6. Intracellular distribution patterns of enzymes in rat-liver tissue. Biochem J. 1955 Aug;60(4):604-17
  2. Johansson AC, Appelqvist H, Nilsson C, Kågedal K, Roberg K, Ollinger K. Regulation of apoptosis-associated lysosomal membrane permeabilization. Apoptosis. 2010 May;15(5):527-40
  3. Repnik U, Turk B. Lysosomal-mitochondrial cross-talk during cell death. Mitochondrion. 2010 Nov;10(6):662-9
  4. Bursch W. The autophagosomal-lysosomal compartment in programmed cell death. Cell Death Differ. 2001 Jun;8(6):569-81
  5. Guicciardi ME, Leist M, Gores GJ. Lysosomes in cell death. Oncogene. 2004 Apr 12;23(16):2881-90
  6. 6.0 6.1 Terman A, Kurz T, Navratil M, Arriaga EA, Brunk UT. Mitochondrial turnover and aging of long-lived postmitotic cells: the mitochondrial-lysosomal axis theory of aging. Antioxid Redox Signal. 2010 Apr;12(4):503-35
  7. Kubota C, Torii S, Hou N, Saito N, Yoshimoto Y, Imai H, Takeuchi T. Constitutive reactive oxygen species generation from autophagosome/lysosome in neuronal oxidative toxicity. J Biol Chem. 2010 Jan 1;285(1):667-74
  8. Ghosh M, Carlsson F, Laskar A, Yuan XM, Li W. Lysosomal membrane permeabilization causes oxidative stress and ferritin induction in macrophages. FEBS Lett. 2011 Feb 18;585(4):623-9
  9. 9.0 9.1 9.2 Hamacher-Brady A, Stein HA, Turschner S, Toegel I, Mora R, Jennewein N, Efferth T, Eils R, Brady NR. Artesunate activates mitochondrial apoptosis in breast cancer cells via iron-catalyzed lysosomal reactive oxygen species production. J Biol Chem. 2011 Feb 25;286(8):6587-601
  10. 10.0 10.1 Loos C, Syrovets T, Musyanovych A, Mailänder V, Landfester K, Nienhaus GU, Simmet T. Functionalized polystyrene nanoparticles as a platform for studying bio-nano interactions. Beilstein J Nanotechnol. 2014 Dec 15;5:2403-12
  11. Wang F, Bexiga MG, Anguissola S, Boya P, Simpson JC, Salvati A, Dawson KA: Time resolved study of cell death mechanisms induced by amine-modified polystyrene nanoparticles. Nanoscale 2013, 5:10868–76
  12. Cho W-S, Duffin R, Howie SEM, Scotton CJ, Wallace WAH, Macnee W, Bradley M, Megson IL, Donaldson K: Progressive severe lung injury by zinc oxide nanoparticles; the role of Zn2+ dissolution inside lysosomes. Part Fibre Toxicol 2011, 8:27
  13. Cho W-S, Duffin R, Thielbeer F, Bradley M, Megson IL, MacNee W, Poland CA, Tran CL, Donaldson K: Zeta potential and solubility to toxic ions as mechanisms of lung inflammation caused by metal/metal oxide nanoparticles. Toxicol Sci 2012, 126:469–477
  14. Cite error: Invalid <ref> tag; no text was provided for refs named Reiners2002
  15. Cite error: Invalid <ref> tag; no text was provided for refs named Li2000
  16. 16.0 16.1 16.2 Kroemer G, Jäättelä M. Lysosomes and autophagy in cell death control. Nat Rev Cancer. 2005 Nov;5(11):886-97
  17. 17.0 17.1 Anguissola S, Garry D, Salvati A, O'Brien PJ, Dawson KA. High content analysis provides mechanistic insights on the pathways of toxicity induced by amine-modified polystyrene nanoparticles. PLoS One. 2014 Sep 19;9(9):e108025
  18. Boya P, Andreau K, Poncet D, Zamzami N, Perfettini JL, Metivier D, Ojcius DM, Jäättelä M, Kroemer G. Lysosomal membrane permeabilization induces cell death in a mitochondrion-dependent fashion. J Exp Med. 2003 May 19;197(10):1323-34
  19. Ghosh M, Carlsson F, Laskar A, Yuan XM, Li W. Lysosomal membrane permeabilization causes oxidative stress and ferritin induction in macrophages. FEBS Lett. 2011 Feb 18;585(4):623-9