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Detection of Lysosomal Membrane Permeabilization
Published in Bruno Gasnier, Michael X. Zhu, Ion and Molecule Transport in Lysosomes, 2020
Anne-Marie Ellegaard, Line Groth-Pedersen, Marja Jäättelä
In addition to lysosomotropic agents discussed above, a wide variety of other drugs and molecules are able to induce LMP (reviewed in (Aits and Jäättelä, 2013; Johansson et al., 2010)). Among these are classical apoptosis-inducers, such as tumour necrosis factor (TNF), tumour protein p53 (TP53) and the pro-apoptotic Bcl-2 family member Bax. While the exact molecular mechanisms responsible for the LMP are unknown, studies of TNF-induced LMP have revealed that it can occur either upstream, downstream or independent of caspase activation (Gyrd-Hansen et al., 2006; Taha et al., 2005), whereas DNA damage-activated TP53 can trigger LMP through direct interaction with lysosome-associated apoptosis-inducing protein containing the pleckstrin homology and FYVE domains on the lysosomal membrane (Li et al., 2007). Akin to the permeabilization of mitochondrial outer membrane in apoptosis, Bax has been suggested to induce LMP by forming pores in the lysosomal membrane (Bové et al., 2014; Feldstein et al., 2006; Guan et al., 2015; Karch et al., 2017). It should, however, be noted that LMP can occur independently of caspase activation, TP53 and Bax (Foghsgaard et al., 2001; Gyrd-Hansen et al., 2006).
Secretory autophagy: a turn key for understanding AMD pathology and developing new therapeutic targets?
Published in Expert Opinion on Therapeutic Targets, 2022
Janusz Blasiak, Kai Kaarniranta
The core set of proteins used for autophagosome synthesis consists of four functional groups: the Unc-51 like autophagy activating kinase 1 (ULK1) complex, class III phosphatidylinositol 3-kinase (PI3KC3), two ubiquitin-like proteins, microtubule-associated protein 1 light chain 3 (LC3) and autophagy-related protein 12 (ATG12), and the membrane cycling protein, ATG9 [10]. Autophagosome formation starts with nucleation of an isolation membrane/phagophore and activation of the ULK1 complex, recruiting ATG proteins. ULK1 stimulates PI3KC3 activity through the phosphorylation of ATG14 and Beclin-1 (BCN1), which supplements the membrane in phosphatidylinositol 3-phosphate (PI3P) and promotes binding of proteins containing the FYVE domain. ATG9 moves to the phagophore to supply lipids for its expansion. ATG8 is incorporated into the phagophore through an E3-like reaction in which the ATG12/ATG5/ATG16 complex conjugates ATG8 to phosphatidylethanolamine (PE). In mammals, the ATG8 family contains six members, including the LC3 and γ-aminobutyric acid receptor associated protein (GABARAP) subfamilies. The lipidation of mammalian ATG8s relies on the two ubiquitin-like conjugation systems [11].
Identification of a novel nonsense variant in FYCO1 gene associated with infantile cataract and cortical atrophy
Published in Ophthalmic Genetics, 2021
Raffi Aprahamian, T. Yammine, N. Salem, M. Souaid, H. Mansour, C. Farra
In 2011, Chen et al. initially reported on loss of fyve and coiled-coil domain containing 1 (FYCO1, #MIM607182) with infantile cataract (4). Recent studies have reported that variants in the FYCO1 gene are associated with autosomal recessive infantile cataract (2). FYCO1 plays an important role in the transport of autophagosomes to lysosomes. FYCO1 gene consists of 18 exons mapping to the common eliminated region 1 (C3CER1) on chromosome 3p21.3 (7). It is a member of the PI(3)P-binding protein family localized to autophagosomes and mediates microtubule plus-end directed vesicles transport (3). The FYCO1 domain structure comprises an α-helical RUN domain (4); an evolutionary conserved protein–protein binding domain which interacts with GTPases (8); four long coiled-coil regions, and a FYVE domain (4), which is a double zinc finger-like domain with a major role in the regulation of various features of endomembrane homeostasis (9); an LC3-interacting region (4), which has a crucial role in the selection of autophagy substrate and autophagosome biogenesis (10); and a Golgi dynamic (GOLD) domain (4). Loss of FYCO1 function inhibits the autophagosomes transport process from the perinuclear area to the periphery, leading to an accumulation of large numbers of vesicles, hence, loss of lens transparency (11).
Caffeine attenuates seizure and brain mitochondrial disruption induced by Tramadol: the role of adenosinergic pathway
Published in Drug and Chemical Toxicology, 2021
Mahedeh Samadi, Fatemeh Shaki, Behnaz Bameri, Marjan Fallah, Nematollah Ahangar, Hamidreza Mohammadi
Mitochondria are the primary site of ROS production in the cell. Many studies have shown that oxidative stress is directly associated with seizures ( Tjaderborn et al.2009, Abdel-Zaher et al.2011 ). On the other hand, seizure can induce mitochondrial damage and increase production of reactive oxygen species leading to prolongation of seizure. It was stated that numerous neurological and neurodevelopmental disorders are associated with mitochondrial dysfunction. WD repeat and FYVE domain-containing 3 (WDFY3) has been demonstrated to have a critical role in mitochondrial homeostasis as well as being associated with neuron differentiation and neurodevelopment (Napoli et al.2018). Therefore, in this case, WDFY3 may partly play a role requiring further evaluations in future studies.