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ATG5 mitophagy

I M Aparicio, J Espino, I Bejarano, A Gallardo-Soler, M L Campo, G M Salido, J A Pariente, F J Peña, J A Tapia
Macroautophagy (hereafter autophagy) is an evolutionarily highly conserved cellular process that participates in the maintenance of intracellular homeostasis through the degradation of most long-lived proteins and entire organelles. Autophagy participates in some reproductive events; however, there are not reports regarding the role of autophagy in the regulation of sperm physiology. Hence, the aim of this study was to investigate whether autophagy-related proteins are present and functionally active in human spermatozoa...
2016: Scientific Reports
Xiaofeng Yao, Shanshan Sha, Yuexia Wang, Xiance Sun, Jun Cao, Jian Kang, Liping Jiang, Min Chen, Yufang Ma
Lysosomal membrane permeabilization (LMP) and subsequently impaired autophagosome degradation was induced in HepG2 cells after treatment with perfluorooctane sulfonate (PFOS) for 24 h in our previous studies. We found that treatment of HepG2 cells with PFOS-induced autophagosome formation at earlier stage (6 h) of treatment in this study. The autophagosome formation inhibitor 3-methyladenine (3-MA) was able to relieve PFOS-induced LMP and release of cathepsin D in HepG2 cells. Knockdown of Spinster 1, a lysosomal membrane permease, attenuated PFOS-induced LMP in HepG2 cells...
September 2016: Toxicological Sciences: An Official Journal of the Society of Toxicology
Raymonde Szargel, Vered Shani, Fatimah Abd Elghani, Lucy N Mekies, Esti Liani, Ruth Rott, Simone Engelender
PTEN-induced putative kinase 1 (PINK1) and parkin are mutated in familial forms of Parkinson's disease and are important in promoting the mitophagy of damaged mitochondria. In this study, we showed that synphilin-1 interacted with PINK1 and was recruited to the mitochondria. Once in the mitochondria, it promoted PINK1-dependent mitophagy, as revealed by Atg5 knockdown experiments and the recruitment of LC3 and Lamp1 to the mitochondria. PINK1-synphilin-1 mitophagy did not depend on PINK1-mediated phosphorylation of synphilin-1 and occurred in the absence of parkin...
June 22, 2016: Human Molecular Genetics
Haiyang Liu, Hong Zhu, Tong Li, Pengfei Zhang, Ning Wang, Xiaodong Sun
PURPOSE: This study investigated the neuroprotective effect against photoreceptor cell death using prolyl-4-hydroxylases inhibitor (PHI), an HIF-1α stabilizer, in experimental retinal detachment (RD). METHODS: RD was created in Brown Norway rats by subretinal injection of 1% sodium hyaluronate. FG-4592 (a PHI, 25 mg/kg) or a vehicle was administered every 2 days with retro-orbital injection. Photoreceptor death was evaluated by TdT-dUTP terminal nick-end labeling (TUNEL) assay 3 days after RD and by the thickness of the outer nuclear layer 7 days after RD...
April 2016: Investigative Ophthalmology & Visual Science
Yu-Chi Su, Goutham Venkata Naga Davuluri, Cheng-Hao Chen, Dong-Che Shiau, Chien-Chin Chen, Chia-Ling Chen, Yee-Shin Lin, Chih-Peng Chang
Hepatocellular carcinoma (HCC) is one of the most common cancers in Taiwan. Although chemotherapy is the primary treatment for HCC patients, drug resistance often leads to clinical failure. Galectin-1 is a beta-galactoside binding lectin which is up-regulated in HCC patients and promotes tumor growth by mediating cancer cell adhesion, migration and proliferation, but its role in chemoresistance of HCC is poorly understood. In this study we found that galectin-1 is able to lead to chemoresistance against cisplatin treatment, and subsequent inhibition has reversed the effect of cell death in HCC cells...
2016: PloS One
Claudio Marcelo Fader, Betiana Nebaí Salassa, Rubén Adrián Grosso, Agustín Nicolás Vergara, María Isabel Colombo
BACKGROUND INFORMATION: In eukaryotic cells, autophagy is considered a lysosomal catabolic process which participates in the degradation of intracellular components in a vacuolar structure termed autolysosome. This pathway plays a significant role in the erythropoiesis process, contributing to the clearance of some organelles (such as mitochondria) that are not necessary in the mature red blood cells. Nevertheless, the role of autophagy in erythrocyte maturation has not been fully established...
April 2016: Biology of the Cell
F Radogna, C Cerella, A Gaigneaux, C Christov, M Dicato, M Diederich
A limiting factor in the therapeutic outcome of children with high-risk neuroblastoma is the intrinsic and acquired resistance to common chemotherapeutic treatments. Here we investigated the molecular mechanisms by which the hemisynthetic cardiac glycoside UNBS1450 overcomes this limitation and induces differential cell death modalities in both neuroblastic and stromal neuroblastoma through stimulation of a cell-type-specific autophagic response eventually leading to apoptosis or necroptosis. In neuroblastic SH-SY5Y cells, we observed a time-dependent production of reactive oxygen species that affects lysosomal integrity inducing lysosome-associated membrane protein 2 degradation and cathepsin B and L activation...
July 21, 2016: Oncogene
Nuo Sun, Jeanho Yun, Jie Liu, Daniela Malide, Chengyu Liu, Ilsa I Rovira, Kira M Holmström, Maria M Fergusson, Young Hyun Yoo, Christian A Combs, Toren Finkel
Alterations in mitophagy have been increasingly linked to aging and age-related diseases. There are, however, no convenient methods to analyze mitophagy in vivo. Here, we describe a transgenic mouse model in which we expressed a mitochondrial-targeted form of the fluorescent reporter Keima (mt-Keima). Keima is a coral-derived protein that exhibits both pH-dependent excitation and resistance to lysosomal proteases. Comparison of a wide range of primary cells and tissues generated from the mt-Keima mouse revealed significant variations in basal mitophagy...
November 19, 2015: Molecular Cell
Zhenqing Zhou, Frans Vinberg, Frank Schottler, Teresa A Doggett, Vladimir J Kefalov, Thomas A Ferguson
Cones comprise only a small portion of the photoreceptors in mammalian retinas. However, cones are vital for color vision and visual perception, and their loss severely diminishes the quality of life for patients with retinal degenerative diseases. Cones function in bright light and have higher demand for energy than rods; yet, the mechanisms that support the energy requirements of cones are poorly understood. One such pathway that potentially could sustain cones under basal and stress conditions is macroautophagy...
2015: Autophagy
Jiyong Liang, Zhi-Xiang Xu, Zhiyong Ding, Yiling Lu, Qinghua Yu, Kaitlin D Werle, Ge Zhou, Yun-Yong Park, Guang Peng, Michael J Gambello, Gordon B Mills
AMP-activated protein kinase (AMPK) plays a central role in cellular energy sensing and bioenergetics. However, the role of AMPK in surveillance of mitochondrial damage and induction of mitophagy remains unclear. We demonstrate herein that AMPK is required for efficient mitophagy. Mitochondrial damage induces a physical association of AMPK with ATG16-ATG5-12 and an AMPK-dependent recruitment of the VPS34 and ATG16 complexes with the mitochondria. Targeting AMPK to the mitochondria is both sufficient to induce mitophagy and to promote cell survival...
2015: Nature Communications
Catherine L Nezich, Chunxin Wang, Adam I Fogel, Richard J Youle
The kinase PINK1 and ubiquitin ligase Parkin can regulate the selective elimination of damaged mitochondria through autophagy (mitophagy). Because of the demand on lysosomal function by mitophagy, we investigated a role for the transcription factor EB (TFEB), a master regulator of lysosomal biogenesis, in this process. We show that during mitophagy TFEB translocates to the nucleus and displays transcriptional activity in a PINK1- and Parkin-dependent manner. MITF and TFE3, homologues of TFEB belonging to the same microphthalmia/transcription factor E (MiT/TFE) family, are similarly regulated during mitophagy...
August 3, 2015: Journal of Cell Biology
Alicia K Au, Yaming Chen, Lina Du, Craig M Smith, Mioara D Manole, Sirine A Baltagi, Charleen T Chu, Rajesh K Aneja, Hülya Bayır, Patrick M Kochanek, Robert S B Clark
Increased autophagy/mitophagy is thought to contribute to cerebellar dysfunction in Purkinje cell degeneration mice. Intriguingly, cerebellar Purkinje cells are highly vulnerable to hypoxia-ischemia (HI), related at least in part to their high metabolic activity. Whether or not excessive or supraphysiologic autophagy plays a role in Purkinje cell susceptibility to HI is unknown. Accordingly, we evaluated the role of autophagy in the cerebellum after global ischemia produced by asphyxial cardiac arrest in postnatal day (PND) 16-18 rats, using siRNA-targeted inhibition of Atg7, necessary for microtubule-associated protein light chain 3-II (LC3-II) and Atg12-Atg5 complex formation...
September 2015: Biochimica et Biophysica Acta
Rikke Kruse, Birgitte F Vind, Stine J Petersson, Jonas M Kristensen, Kurt Højlund
AIMS/HYPOTHESIS: Autophagy is a catabolic process that maintains cellular homeostasis by degradation of protein aggregates and selective removal of damaged organelles, e.g. mitochondria (mitophagy). Insulin resistance in skeletal muscle has been linked to mitochondrial dysfunction and altered protein metabolism. Here, we investigated whether abnormalities in autophagy are present in human muscle in obesity and type 2 diabetes. METHODS: Using a case-control design, skeletal muscle biopsies obtained in the basal and insulin-stimulated states from patients with type 2 diabetes during both euglycaemia and hyperglycaemia, and from glucose-tolerant lean and obese individuals during euglycaemia, were used for analysis of mRNA levels, protein abundance and phosphorylation of autophagy-related proteins...
September 2015: Diabetologia
Jie Li, Wei Qi, Guo Chen, Du Feng, Jinhua Liu, Biao Ma, Changqian Zhou, Chenglong Mu, Weilin Zhang, Quan Chen, Yushan Zhu
Mitochondria serve as membrane sources and signaling platforms for regulating autophagy. Accumulating evidence has also shown that damaged mitochondria are removed through both selective mitophagy and general autophagy in response to mitochondrial and oxidative stresses. Protein ubiquitination through mitochondrial E3 ligases plays an integrative role in mitochondrial outer membrane protein degradation, mitochondrial dynamics, and mitophagy. Here we showed that MUL1, a mitochondria-localized E3 ligase, regulates selenite-induced mitophagy in an ATG5 and ULK1-dependent manner...
2015: Autophagy
Yuki Tamura, Yu Kitaoka, Yutaka Matsunaga, Daisuke Hoshino, Hideo Hatta
KEY POINTS: Traumatic nerve injury or nerve disease leads to denervation and severe muscle atrophy. Recent evidence shows that mitochondrial loss could be a key mediator of skeletal muscle atrophy. Here, we show that daily heat stress treatment rescues denervation-induced loss of mitochondria and concomitant muscle atrophy. We also found that denervation-activated autophagy-dependent mitochondrial clearance (mitophagy) was suppressed by daily heat stress treatment. The molecular basis of this observation is explained by our results showing that heat stress treatment attenuates the increase of key proteins that regulate the tagging step for mitochondrial clearance and the intermediate step of autophagosome formation in denervated muscle...
June 15, 2015: Journal of Physiology
Yuko Hirota, Shun-ichi Yamashita, Yusuke Kurihara, Xiulian Jin, Masamune Aihara, Tetsu Saigusa, Dongchon Kang, Tomotake Kanki
In cultured cells, not many mitochondria are degraded by mitophagy induced by physiological cellular stress. We observed mitophagy in HeLa cells using a method that relies on the pH-sensitive fluorescent protein Keima. With this approach, we found that mitophagy was barely induced by carbonyl cyanide m-chlorophenyl hydrazone treatment, which is widely used as an inducer of PARK2/Parkin-related mitophagy, whereas a small but modest amount of mitochondria were degraded by mitophagy under conditions of starvation or hypoxia...
2015: Autophagy
Luis Bonet-Ponce, Sara Saez-Atienzar, Carmen da Casa, Miguel Flores-Bellver, Jorge M Barcia, Javier Sancho-Pelluz, Francisco J Romero, Joaquín Jordan, María F Galindo
We have explored the mechanisms underlying ethanol-induced mitochondrial dynamics disruption and mitophagy. Ethanol increases mitochondrial fission in a concentration-dependent manner through Drp1 mitochondrial translocation and OPA1 proteolytic cleavage. ARPE-19 (a human retinal pigment epithelial cell line) cells challenged with ethanol showed mitochondrial potential disruptions mediated by alterations in mitochondrial complex IV protein level and increases in mitochondrial reactive oxygen species production...
July 2015: Biochimica et Biophysica Acta
Benjamin Cull, Joseane Lima Prado Godinho, Juliany Cola Fernandes Rodrigues, Benjamin Frank, Uta Schurigt, Roderick Am Williams, Graham H Coombs, Jeremy C Mottram
Autophagy is a central process behind the cellular remodeling that occurs during differentiation of Leishmania, yet the cargo of the protozoan parasite's autophagosome is unknown. We have identified glycosomes, peroxisome-like organelles that uniquely compartmentalize glycolytic and other metabolic enzymes in Leishmania and other kinetoplastid parasitic protozoa, as autophagosome cargo. It has been proposed that the number of glycosomes and their content change during the Leishmania life cycle as a key adaptation to the different environments encountered...
2014: Autophagy
Rodrigo Troncoso, Felipe Paredes, Valentina Parra, Damián Gatica, César Vásquez-Trincado, Clara Quiroga, Roberto Bravo-Sagua, Camila López-Crisosto, Andrea E Rodriguez, Alejandra P Oyarzún, Guido Kroemer, Sergio Lavandero
Glucocorticoids, such as dexamethasone, enhance protein breakdown via ubiquitin-proteasome system. However, the role of autophagy in organelle and protein turnover in the glucocorticoid-dependent atrophy program remains unknown. Here, we show that dexamethasone stimulates an early activation of autophagy in L6 myotubes depending on protein kinase, AMPK, and glucocorticoid receptor activity. Dexamethasone increases expression of several autophagy genes, including ATG5, LC3, BECN1, and SQSTM1 and triggers AMPK-dependent mitochondrial fragmentation associated with increased DNM1L protein levels...
2014: Cell Cycle
Jing Zou, Fei Yue, Wenjiao Li, Kun Song, Xianhan Jiang, Jinglin Yi, Leyuan Liu
Autophagy plays an important role in tumorigenesis. Mitochondrion-associated protein LRPPRC interacts with MAP1S that interacts with LC3 and bridges autophagy components with microtubules and mitochondria to affect autophagy flux. Dysfunction of LRPPRC and MAP1S is associated with poor survival of ovarian cancer patients. Furthermore, elevated levels of LRPPRC predict shorter overall survival in patients with prostate adenocarcinomas or gastric cancer. To understand the role of LRPPRC in tumor development, previously we reported that LRPPRC forms a ternary complex with Beclin 1 and Bcl-2 to inhibit autophagy...
2014: PloS One
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