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https://www.readbyqxmd.com/read/29054108/increase-in-pro-apoptotic-activity-of-inhibitory-pas-domain-protein-via-phosphorylation-by-mk2
#1
Shuya Kasai, Mary Jane Elizabeth Richardson, Satoru Torii, Ken-Ichi Yasumoto, Hiroki Shima, Kazuhiko Igarashi, Ken Itoh, Kazuhiro Sogawa, Kazutaka Murayama
Inhibitory PAS domain protein (IPAS) is a bifunctional protein that downregulates hypoxic gene expression and exerts pro-apoptotic activity by preventing pro-survival activity of Bcl-xL and its related factors. Pro-apoptotic activity of IPAS is attenuated by the activation of the PINK1-Parkin pathway, and involved in neuronal degeneration in an experimental mouse model of Parkinson's disease. The current study shows that phosphorylation of IPAS at Ser184 by MAPK-activated protein kinase 2 (MK2 or MAPKAPK2) enhances the pro-apoptotic function of IPAS...
October 20, 2017: FEBS Journal
https://www.readbyqxmd.com/read/29050400/metformin-reverses-trap1-mutation-associated-alterations-in-mitochondrial-function-in-parkinson-s-disease
#2
Julia C Fitzgerald, Alexander Zimprich, Daniel A Carvajal Berrio, Kevin M Schindler, Brigitte Maurer, Claudia Schulte, Christine Bus, Anne-Kathrin Hauser, Manuela Kübler, Rahel Lewin, Dheeraj Reddy Bobbili, Lisa M Schwarz, Evangelia Vartholomaiou, Kathrin Brockmann, Richard Wüst, Johannes Madlung, Alfred Nordheim, Olaf Riess, L Miguel Martins, Enrico Glaab, Patrick May, Katja Schenke-Layland, Didier Picard, Manu Sharma, Thomas Gasser, Rejko Krüger
The mitochondrial proteins TRAP1 and HTRA2 have previously been shown to be phosphorylated in the presence of the Parkinson's disease kinase PINK1 but the downstream signalling is unknown. HTRA2 and PINK1 loss of function causes parkinsonism in humans and animals. Here, we identified TRAP1 as an interactor of HTRA2 using an unbiased mass spectrometry approach. In our human cell models, TRAP1 overexpression is protective, rescuing HTRA2 and PINK1-associated mitochondrial dysfunction and suggesting that TRAP1 acts downstream of HTRA2 and PINK1...
September 1, 2017: Brain: a Journal of Neurology
https://www.readbyqxmd.com/read/29036556/deficit-in-pink1-parkin-mediated-mitochondrial-autophagy-at-late-stages-of-dystrophic-cardiomyopathy
#3
Chifei Kang, Myriam A Badr, Viktoriia Kyrychenko, Eeva-Liisa Eskelinen, Natalia Shirokova
Aims: Duchenne Muscular Dystrophy (DMD) is an inherited devastating muscle disease with severe and often lethal cardiac complications. Emerging evidence suggests that the evolution of the pathology in DMD is accompanied by the accumulation of mitochondria with defective structure and function. Here we investigate whether defects in the housekeeping autophagic pathway contribute to mitochondrial and metabolic dysfunctions in dystrophic cardiomyopathy. Methods and results: We employed various biochemical and imaging techniques to assess mitochondrial structure and function as well as to evaluate autophagy, and specific mitochondrial autophagy (mitophagy), in hearts of mdx mice, an animal model of DMD...
October 5, 2017: Cardiovascular Research
https://www.readbyqxmd.com/read/29033320/mitophagy-controls-the-activities-of-tumor-suppressor-p53-to-regulate-hepatic-cancer-stem-cells
#4
Kai Liu, Jiyoung Lee, Ja Yeon Kim, Linya Wang, Yongjun Tian, Stephanie T Chan, Cecilia Cho, Keigo Machida, Dexi Chen, Jing-Hsiung James Ou
Autophagy is required for benign hepatic tumors to progress into malignant hepatocellular carcinoma. However, the mechanism is unclear. Here, we report that mitophagy, the selective removal of mitochondria by autophagy, positively regulates hepatic cancer stem cells (CSCs) by suppressing the tumor suppressor p53. When mitophagy is enhanced, p53 co-localizes with mitochondria and is removed by a mitophagy-dependent manner. However, when mitophagy is inhibited, p53 is phosphorylated at serine-392 by PINK1, a kinase associated with mitophagy, on mitochondria and translocated into the nucleus, where it binds to the NANOG promoter to prevent OCT4 and SOX2 transcription factors from activating the expression of NANOG, a transcription factor critical for maintaining the stemness and the self-renewal ability of CSCs, resulting in the reduction of hepatic CSC populations...
October 19, 2017: Molecular Cell
https://www.readbyqxmd.com/read/29028772/heme-oxygenase-1-protects-the-liver-from-septic-injury-by-modulating-tlr4-mediated-mitochondrial-quality-control-in-mice
#5
Jin-Sook Park, Hyo-Sun Choi, So-Yeon Yim, Sun-Mee Lee
Mitochondrial dysfunction is involved in the pathogenesis of sepsis-induced multiple organ dysfunction syndrome (MODS). Mitochondrial quality control (QC) is characterized by self-recovering mitochondrial damage through mitochondrial biogenesis, mitophagy, and fission/fusion. Heme oxygenase (HO)-1 acts as a signaling molecule to modulate inflammation. The present study elucidated the cytoprotective mechanisms of HO-1 in sepsis, particularly focusing on toll-like receptor (TLR)4-mediated mitochondrial QC. Mice were subjected to sepsis by cecal ligation and puncture (CLP)...
October 12, 2017: Shock
https://www.readbyqxmd.com/read/29025974/lipid-based-dna-sirna-transfection-agents-disrupt-neuronal-bioenergetics-and-mitophagy
#6
Eleonora Napoli, Siming Liu, Ilaria Marsilio, Konstantinos Zarbalis, Cecilia Giulivi
A multitude of natural and artificial compounds have been recognized to modulate autophagy, providing direct or, through associated pathways, indirect entry points to activation and inhibition. While these pharmacological tools are extremely useful in the study of autophagy, their abundance also suggests the potential presence of unidentified autophagic modulators that may interfere with experimental designs if applied unknowingly. Here, we report unanticipated effects on autophagy and bioenergetics in neuronal progenitor cells (NPC) incubated with widely used lipid-based-transfection reagent lipofectamine (LF), which induced mitochondria depolarization followed by disruption of electron transport...
October 12, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/29022898/superoxide-drives-progression-of-parkin-pink1-dependent-mitophagy-following-translocation-of-parkin-to-mitochondria
#7
Bin Xiao, Xiao Deng, Grace G Y Lim, Shaoping Xie, Zhi Dong Zhou, Kah-Leong Lim, Eng-King Tan
Reactive oxygen species (ROS) and mitophagy are profoundly implicated in the pathogenesis of neurodegenerative diseases, such as Parkinson's disease (PD). Several studies have suggested that ROS are not involved in mitochondrial translocation of Parkin which primes mitochondria for autophagic elimination. However, whether ROS play a role in the execution of mitophagy is unknown. In the present study, we show that carbonyl cyanide m-chlorophenylhydrazone (CCCP) treatment induced both mitochondrial depolarization and generation of ROS that were needed for the mitophagy process...
October 12, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/29022200/high-expression-of-the-mitophagy-related-protein-pink1-is-associated-with-a-poor-response-to-chemotherapy-and-a-poor-prognosis-for-patients-treated-with-neoadjuvant-chemotherapy-for-esophageal-squamous-cell-carcinoma
#8
Kotaro Yamashita, Hiroshi Miyata, Tomoki Makino, Yasunori Masuike, Haruna Furukawa, Koji Tanaka, Yasuhiro Miyazaki, Tsuyoshi Takahashi, Yukinori Kurokawa, Makoto Yamasaki, Kiyokazu Nakajima, Shuji Takiguchi, Eiichi Morii, Masaki Mori, Yuichiro Doki
BACKGROUND: Autophagy plays a major role in cellular homeostasis and is implicated in cancer progression. Damaged mitochondria are scavenged and eliminated by mitochondrial autophagy, referred to as mitophagy, which can promote cancer cell survival. This study investigated the expression and effects of the autophagy-related protein LC3 and the mitophagy-related protein Pink1 in human esophageal squamous cell carcinoma (ESCC). METHODS: Both LC3 and Pink1 were analyzed by immunohistochemistry in tissues from 217 ESCC patients, including 159 patients undergoing neoadjuvant chemotherapy...
October 11, 2017: Annals of Surgical Oncology
https://www.readbyqxmd.com/read/28993273/acute-mental-stress-induces-mitochondrial-bioenergetic-crisis-and-hyper-fission-along-with-aberrant-mitophagy-in-the-gut-mucosa-in-rodent-model-of-stress-related-mucosal-disease
#9
Rudranil De, Somnath Mazumder, Souvik Sarkar, Subhashis Debsharma, Asim Azhar Siddiqui, Shubhra Jyoti Saha, Chinmoy Banerjee, Shiladitya Nag, Debanjan Saha, Uday Bandyopadhyay
Psychological stress, depression and anxiety lead to multiple organ dysfunctions wherein stress-related mucosal disease (SRMD) is common to people experiencing stress and also occur as a side effect in patients admitted to intensive care units; however the underlying molecular aetiology is still obscure. We report that in rat-SRMD model, cold restraint-stress severely damaged gut mitochondrial functions to generate superoxide anion (O2(•-)), depletion of ATP and shifted mitochondrial fission-fusion dynamics towards enhanced fission to induce mucosal injury...
October 6, 2017: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/28992584/ogt-related-mitochondrial-motility-is-associated-with-sex-differences-and-exercise-effects-in-depression-induced-by-prenatal-exposure-to-glucocorticoids
#10
Weina Liu, Hongmei Wang, Xiangli Xue, Jie Xia, Jiatong Liu, Zhengtang Qi, Liu Ji
BACKGROUND: Prenatal exposure to glucocorticoids (GCs) has been found to trigger abnormal behaviors and deleterious neurological effects on offspring both in animals and in humans. The sex differences in depression have been replicated in numerous studies across cultures, persisting throughout the reproductive years. As an X-linked gene in rodents and in humans, O-GlcNAc transferase (OGT) may provide a novel perspective for the sex differences in depression. METHODS: In the last third of pregnancy (gestational day 14-21), rats were subcutaneously administered either 0...
September 29, 2017: Journal of Affective Disorders
https://www.readbyqxmd.com/read/28991239/stendomycin-selectively-inhibits-tim23-dependent-mitochondrial-protein-import
#11
Ireos Filipuzzi, Janos Steffen, Mitchel Germain, Laetitia Goepfert, Michael A Conti, Christoph Potting, Raffaele Cerino, Martin Pfeifer, Philipp Krastel, Dominic Hoepfner, Julie Bastien, Carla M Koehler, Stephen B Helliwell
Tim17 and Tim23 are the main subunits of the TIM23 complex, one of the two major essential mitochondrial inner-membrane protein translocon machineries (TIMs). No chemical probes that specifically inhibit TIM23-dependent protein import were known to exist. Here we show that the natural product stendomycin, produced by Streptomyces hygroscopicus, is a potent and specific inhibitor of the TIM23 complex in yeast and mammalian cells. Furthermore, stendomycin-mediated blockage of the TIM23 complex does not alter normal processing of the major regulatory mitophagy kinase PINK1, but TIM23 is required to stabilize PINK1 on the outside of mitochondria to initiate mitophagy upon membrane depolarization...
October 9, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28984592/tomm40-and-apoe-gene-expression-and-cognitive-decline-in-japanese-alzheimer-s-disease-subjects
#12
Ayano Mise, Yuta Yoshino, Kiyohiro Yamazaki, Yuki Ozaki, Tomoko Sao, Taku Yoshida, Takaaki Mori, Yoko Mori, Shinichiro Ochi, Jun-Ichi Iga, Shu-Ichi Ueno
BACKGROUND: TOMM40 is located on chromosome 19, is in linkage disequilibrium with apolipoprotein E (APOE), andis reported in several genome-wide association studies to be associated with Alzheimer's disease (AD). OBJECTIVE: Assess APOE and TOM40 and mitochondrial genes as blood biomarkers for AD. METHODS: We examined TOMM40, PTEN-induced putative kinase 1 (PINK1), Parkin RBR E3 ubiquitin protein ligase (PARK2), and APOE mRNA expression in relation to the methylation rates of CpG sites in the upstream region of TOMM40exon 1 in peripheral leukocytes and TOMM40523 polyT genotypes in 60 AD and age- and sex-matched control subjects...
2017: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/28980524/structure-of-pink1-and-mechanisms-of-parkinson-s-disease-associated-mutations
#13
Atul Kumar, Jevgenia Tamjar, Andrew D Waddell, Helen I Woodroof, Olawale G Raimi, Andrew M Shaw, Mark Peggie, Miratul Mk Muqit, Daan Mf van Aalten
Mutations in the human kinase PINK1 (hPINK1) are associated with autosomal recessive early-onset Parkinson's disease (PD). hPINK1 activates Parkin E3 ligase activity, involving phosphorylation of ubiquitin and the Parkin ubiquitin-like (Ubl) domain via as yet poorly understood mechanisms. hPINK1 is unusual amongst kinases due to the presence of three loop insertions of unknown function. We report the structure of Tribolium castaneum PINK1 (TcPINK1), revealing several unique extensions to the canonical protein kinase fold...
October 5, 2017: ELife
https://www.readbyqxmd.com/read/28978077/am1241-alleviates-mptp-induced-parkinson-s-disease-and-promotes-the-regeneration-of-da-neurons-in-pd-mice
#14
Jun Shi, Qiong Cai, Jingxing Zhang, Xiaolie He, Yigang Liu, Rongrong Zhu, Lingjing Jin
The main pathological feature of Parkinson's disease (PD) is the loss of dopaminergic neurons in the substantia nigra. In this study, we investigated the role of cannabinoid receptor 2 (CB2R) agonist AM1241 on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity in a mouse model of PD. Upon treatment with AM1241, the decreased CB2R level in the PD mouse brain was reversed and the behavior score markedly elevated, accompanied with a dose-dependent increase of dopamine and serotonin. In addition, western blot assay and immunostaining results suggested that AM1241 significantly activated PI3K/Akt/MEK phosphorylation and increased the expression of Parkin and PINK1, both in the substantia nigra and hippocampus...
September 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28976028/unraveling-pink1-regulation-ubiquitination-of-its-mature-form-and-insights-for-parkinson-s-disease
#15
Usman Saeed, Mario Masellis
No abstract text is available yet for this article.
October 4, 2017: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/28975445/from-autophagy-to-mitophagy-the-roles-of-p62-in-neurodegenerative-diseases
#16
REVIEW
Haiying Liu, Chunqiu Dai, Yunlong Fan, Baolin Guo, Keke Ren, Tangna Sun, Wenting Wang
P62, also called sequestosome1 (SQSTM1), is the selective cargo receptor for autophagy to degenerate misfolded proteins. It has also been found to assist and connect parkin in pink1/parkin mitophagy pathway. Previous studies showed that p62 was in association with neurodegenerative diseases, and one of the diseases pathogenesis is P62 induced autophagy and mitophagy dysfunction. Autophagy is an important process to eliminate misfolded proteins. Intracellular aggregation including α-synuclein, Huntingtin, tau protein and ß-amyloid (Aß) protein are the misfolded proteins found in PD, HD and AD, respectively...
October 3, 2017: Journal of Bioenergetics and Biomembranes
https://www.readbyqxmd.com/read/28974925/commentary-nix-restores-mitophagy-and-mitochondrial-function-to-protect-against-pink1-parkin-related-parkinson-s-disease
#17
COMMENT
Jin-Sung Park, Brianada Koentjoro, Carolyn M Sue
No abstract text is available yet for this article.
2017: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/28973175/amyotrophic-lateral-sclerosis-associated-mutant-sod1-inhibits-anterograde-axonal-transport-of-mitochondria-by-reducing-miro1-levels
#18
Annekathrin Moller, Claudia S Bauer, Rebecca N Cohen, Christopher P Webster, Kurt J De Vos
Defective axonal transport is an early neuropathological feature of amyotrophic lateral sclerosis (ALS). We have previously shown that ALS-associated mutations in Cu/Zn superoxide dismutase 1 (SOD1) impair axonal transport of mitochondria in motor neurons isolated from SOD1 G93A transgenic mice and in ALS mutant SOD1 transfected cortical neurons, but the underlying mechanisms remained unresolved.The outer mitochondrial membrane protein mitochondrial Rho GTPase 1 (Miro1) is a master regulator of mitochondrial axonal transport in response to cytosolic calcium (Ca2+) levels ([Ca2+]c) and mitochondrial damage...
September 14, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28962651/hexokinases-link-dj-1-to-the-pink1-parkin-pathway
#19
David N Hauser, Adamantios Mamais, Melissa M Conti, Christopher T Primiani, Ravindran Kumaran, Allissa A Dillman, Rebekah G Langston, Alexandra Beilina, Joseph H Garcia, Alberto Diaz-Ruiz, Michel Bernier, Fabienne C Fiesel, Xu Hou, Wolfdieter Springer, Yan Li, Rafael de Cabo, Mark R Cookson
BACKGROUND: Early onset Parkinson's disease is caused by variants in PINK1, parkin, and DJ-1. PINK1 and parkin operate in pathways that preserve mitochondrial integrity, but the function of DJ-1 and how it relates to PINK1 and parkin is poorly understood. METHODS: A series of unbiased high-content screens were used to analyze changes at the protein, RNA, and metabolite level in rodent brains lacking DJ-1. Results were validated using targeted approaches, and cellular assays were performed to probe the mechanisms involved...
September 29, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28945249/mechanism-and-regulation-of-the-lys6-selective-deubiquitinase-usp30
#20
Malte Gersch, Christina Gladkova, Alexander F Schubert, Martin A Michel, Sarah Maslen, David Komander
Damaged mitochondria undergo mitophagy, a specialized form of autophagy that is initiated by the protein kinase PINK1 and the ubiquitin E3 ligase Parkin. Ubiquitin-specific protease USP30 antagonizes Parkin-mediated ubiquitination events on mitochondria and is a key negative regulator of mitophagy. Parkin and USP30 both show a preference for assembly or disassembly, respectively, of Lys6-linked polyubiquitin, a chain type that has not been well studied. Here we report crystal structures of human USP30 bound to monoubiquitin and Lys6-linked diubiquitin, which explain how USP30 achieves Lys6-linkage preference through unique ubiquitin binding interfaces...
September 25, 2017: Nature Structural & Molecular Biology
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