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Wei Liu, Xiuying Duan, Xuefei Fang, Weina Shang, Chao Tong
Neurodegeneration is characterized by protein aggregate deposits and mitochondrial malfunction. Reduction in Tom40 (translocase of outer membrane 40) expression, a key subunit of the translocase of the outer mitochondrial membrane complex, led to accumulation of ubiquitin (Ub)-positive protein aggregates engulfed by Atg8a-positive membranes. Other macroautophagy markers were also abnormally accumulated. Autophagy was induced but the majority of autophagosomes failed to fuse with lysosomes when Tom40 was downregulated...
June 18, 2018: Autophagy
Elena Marcassa, Andreas Kallinos, Jane Jardine, Emma V Rusilowicz-Jones, Aitor Martinez, Sandra Kuehl, Markus Islinger, Michael J Clague, Sylvie Urbé
USP30 is an integral protein of the outer mitochondrial membrane that counteracts PINK1 and Parkin-dependent mitophagy following acute mitochondrial depolarisation. Here, we use two distinct mitophagy reporter systems to reveal tonic suppression by USP30, of a PINK1-dependent component of basal mitophagy in cells lacking detectable Parkin. We propose that USP30 acts upstream of PINK1 through modulation of PINK1-substrate availability and thereby determines the potential for mitophagy initiation. We further show that a fraction of endogenous USP30 is independently targeted to peroxisomes where it regulates basal pexophagy in a PINK1- and Parkin-independent manner...
June 12, 2018: EMBO Reports
Marc P M Soutar, Liam Kempthorne, Shuichi Miyakawa, Emily Annuario, Daniela Melandri, Jasmine Harley, Gregory A O'Sullivan, Selina Wray, David C Hancock, Mark R Cookson, Julian Downward, Mark Carlton, Hélène Plun-Favreau
The discovery of mutations within genes associated with autosomal recessive Parkinson's disease allowed for the identification of PINK1/Parkin regulated mitophagy as an important pathway for the removal of damaged mitochondria. While recent studies suggest that AKT-dependent signalling regulates Parkin recruitment to depolarised mitochondria, little is known as to whether this can also regulate PINK1 mitochondrial accumulation and downstream mitophagy. Here, we demonstrate that inhibition of AKT signalling decreases endogenous PINK1 accumulation in response to mitochondria depolarisation, subsequent Parkin recruitment, phosphorylation of ubiquitin, and ultimately mitophagy...
June 11, 2018: Scientific Reports
Yiyang Wang, Jieliang Shen, Yanyang Chen, Huzhe Liu, Hao Zhou, Zhibiao Bai, Zhenming Hu
Intervertebral disc degeneration (IDD) is closely related with aging, whereas mitochondrial dysfunction is a common feature of aging in which results cell senescence. Phosphatase and tensin homolog (PTEN)-induced putative kinase protein 1 (PINK1) is a mitochondrial-targeted serine/threonine kinase, which plays a protective role against mitochondrial dysfunction with mitochondrial quality control by activating PINK1/Parkin mediated mitophagy. This study aimed to investigate the protective role of PINK1 against mitochondrial dysfunction and human nucleus pulposus cell (NPC) senescence...
June 8, 2018: Biochemical and Biophysical Research Communications
Shin-Ichi Oka
No abstract text is available yet for this article.
September 1, 2018: International Journal of Cardiology
Wenjun Xiong, Jinghai Hua, Zuheng Liu, Wanqiang Cai, Yujia Bai, Qiong Zhan, Wenyan Lai, Qingchun Zeng, Hao Ren, Dingli Xu
BACKGROUND: Mitochondrial quality control is crucial to the development of angiotensin II (AngII)-induced cardiac hypertrophy. PTEN induced putative kinase 1 (PINK1) is rapidly degraded in normal mitochondria but accumulates in damaged mitochondria, triggering autophagy to protect cells. PINK1 mediates mitophagy in general, but whether PINK1 mediates AngII-induced mitophagy and the effects of PINK1 on AngII-induced injury are unknown. This study was designed to investigate the function of PINK1 in an AngII stimulation model and its regulation of AngII-induced mitophagy...
September 1, 2018: International Journal of Cardiology
Monica Diez-Fairen, Bruno A Benitez, Sara Ortega-Cubero, Oswaldo Lorenzo-Betancor, Carlos Cruchaga, Elena Lorenzo, Lluis Samaranch, Maria Carcel, Jose A Obeso, Maria Cruz Rodriguez-Oroz, Miquel Aguilar, Francisco Coria, Maria A Pastor, Pau Pastor
Eighteen loci and several susceptibility genes have been related to Parkinson's disease (PD). However, most studies focus on single genes in small PD series. Our aim was to establish the genetic background of a large Spanish PD sample. Pooled-DNA target sequencing of 7 major PD genes (SNCA, PARK2, PINK1, DJ-1, LRRK2, GBA, and MAPT) was performed in 562 PD cases. Forty-four variants were found among 114 individuals (20.28%, p<0.05). Among these variants, 30 were found in Mendelian genes (68.18%) and 14 in PD susceptibility genes (31...
May 14, 2018: Neurobiology of Aging
Jorge S Valadas, Giovanni Esposito, Dirk Vandekerkhove, Katarzyna Miskiewicz, Liesbeth Deaulmerie, Susanna Raitano, Philip Seibler, Christine Klein, Patrik Verstreken
Parkinson's disease patients report disturbed sleep patterns long before motor dysfunction. Here, in parkin and pink1 models, we identify circadian rhythm and sleep pattern defects and map these to specific neuropeptidergic neurons in fly models and in hypothalamic neurons differentiated from patient induced pluripotent stem cells (iPSCs). Parkin and Pink1 control the clearance of mitochondria by protein ubiquitination. Although we do not observe major defects in mitochondria of mutant neuropeptidergic neurons, we do find an excess of endoplasmic reticulum-mitochondrial contacts...
June 1, 2018: Neuron
Kou Motani, Hidetaka Kosako
Protein phosphorylation is one of the most common post-translational modifications in eukaryotes and can regulate diverse properties of proteins. Protein kinases are encoded by more than 500 genes in higher eukaryotes and play central roles in various cellular signaling pathways. Consequently, genetic abnormalities of protein kinases have been implicated in many diseases. To fully understand the complex phosphorylation-mediated signaling networks, it is important to globally identify and functionally characterize in vivo substrates of individual protein kinases...
June 5, 2018: Biochimica et Biophysica Acta
Fenglei Jian, Dan Chen, Li Chen, Chaojun Yan, Bin Lu, Yushan Zhu, Shi Chen, Anbing Shi, David C Chan, Zhiyin Song
PINK1 and Parkin mediate mitophagy, the cellular process that clears dysfunctional mitochondria. Mitophagy is regulated by mitochondrial dynamics, but the molecules linking these two processes remain poorly understood. Here, we show that Sam50, the core component of the sorting and assembly machinery (SAM), is a critical regulator of mitochondrial dynamics and PINK1-Parkin-mediated mitophagy. In response to Sam50 depletion, normal tubular mitochondria are first fragmented and subsequently merged into large spheres...
June 5, 2018: Cell Reports
Huang Deyu, Cui Luqing, Liu Xianglian, Guo Pu, Lu Qirong, Wang Xu, Yuan Zonghui
T-2 toxin is the most toxic member of trichothecene mycotoxin. So far, the mechanism of mitochondrial toxicity and protective mechanism in mammalian cells against T-2 toxin are not fully understood. In this study, we aimed to investigate the cellular and mitochondrial toxicity of T-2 toxin, and the cellular protective mechanisms in rat pituitary GH3 cells. We showed that T-2 toxin significantly increased reactive oxygen species (ROS) and DNA damage and caused apoptosis in GH3 cells. T-2 toxin induced abnormal cell morphology, cytoplasm and nuclear shrinkage, nuclear fragmentation and formation of apoptotic bodies and autophagosomes...
June 2, 2018: Toxicology Letters
Mei-Fang Jin, Hong Ni, Li-Li Li
Developmental seizure-induced long-term neuronal hyperexcitation is partially mediated by regenerative mossy fiber sprouting in hippocampus. Yet, there are no effective drugs available to block this pathological process. Recently, leptin has been shown to prevent the sprouting of hippocampal mossy fibers and abnormalities in the neurobehavioral parameters. However, their underlying molecular mechanisms are largely unknown. The purpose of this study was to determine the effect of glutamate on the parameters of zinc homeostasis, mitochondrial functions, and mitophagy regulating factors, as well as to investigate the protective effects of leptin against cytotoxicity of glutamate in murine HT22 hippocampal neuronal cells...
2018: Frontiers in Neurology
Zhihao Wu, Yan Wang, Junghyun Lim, Boxiang Liu, Yanping Li, Rasika Vartak, Trisha Stankiewicz, Stephen Montgomery, Bingwei Lu
Translation of mRNAs is tightly regulated and constantly surveyed for errors. Aberrant translation can trigger co-translational protein and RNA quality control processes, impairments of which cause neurodegeneration by still poorly understood mechanism(s). Here we show that quality control of translation of mitochondrial outer membrane (MOM)-localized mRNA intersects with the turnover of damaged mitochondria, both orchestrated by the mitochondrial kinase PINK1. Mitochondrial damage causes stalled translation of complex-I 30 kDa subunit (C-I30) mRNA on MOM, triggering the recruitment of co-translational quality control factors Pelo, ABCE1, and NOT4 to the ribosome/mRNA-ribonucleoprotein complex...
May 18, 2018: Cell Metabolism
Wei Cheng, Fei Zhao, Cheng-Yuan Tang, Xu-Wei Li, Min Luo, Shao-Bin Duan
Recent progress in angiography and interventional therapy has revived interest in comparison of nephrotoxicity of low-or iso-osmolar contrast media, but detailed mechanisms and effective treatments of contrast-induced acute kidney injury (CI-AKI) remain elusive. We established a new model of CI-AKI and compared the nephrotoxicity of iohexol and iodixanol with a focus on renal oxidative stress, mitochondrial damage and mitophagy. Our results showed that 48-h dehydration plus furosemide injection before iohexol administration successfully induced CI-AKI in rats...
June 2, 2018: Archives of Toxicology
Sándor Márki, Anikó Göblös, Eszter Szlávicz, Nóra Török, Péter Balicza, Benjamin Bereznai, Annamária Takáts, József Engelhardt, Péter Klivényi, László Vécsei, Mária Judit Molnár, Nikoletta Nagy, Márta Széll
Parkinson's disease (PD) is a common neurodegenerative disorder characterized by bradykinesia, resting tremor, and muscle rigidity. To date, approximately 50 genes have been implicated in PD pathogenesis, including both Mendelian genes with rare mutations and low-penetrance genes with common polymorphisms. Previous studies of low-penetrance genes focused on protein-coding genes, and less attention was given to long noncoding RNAs (lncRNAs). In this study, we aimed to investigate the susceptibility roles of lncRNA gene polymorphisms in the development of PD...
2018: Parkinson's Disease
Lingling Lu, Huanzhen Jia, Ge Gao, Chunli Duan, Jing Ren, Yi Li, Hui Yang
PTEN induced putative kinase 1 (PINK1), also known as PARK6, is causally linked to familial Parkinsonism, and heterozygous loss of PINK1 is a risk factor for sporadic Parkinson's disease. However, little is known about its physiological function. Its deficiency was shown to decrease dopamine without significant loss of dopaminergic neurons. We investigated the mechanistic basis for this observation in the present study using dopaminergic MN9D cells. We found that PINK1 knockdown resulted in dopamine content to decrease with suppressed tyrosine hydroxylase expression in cells...
May 18, 2018: Journal of Alzheimer's Disease: JAD
Tom Cornelissen, Sven Vilain, Katlijn Vints, Natalia Gounko, Patrik Verstreken, Wim Vandenberghe
Mutations in the genes for PINK1 and parkin cause Parkinson's disease. PINK1 and parkin cooperate in the selective autophagic degradation of damaged mitochondria (mitophagy) in cultured cells. However, evidence for their role in mitophagy in vivo is still scarce. Here, we generated a Drosophila model expressing the mitophagy probe mt-Keima. Using live mt-Keima imaging and correlative light and electron microscopy (CLEM) we show that mitophagy occurs in muscle cells and dopaminergic neurons in vivo, even in the absence of exogenous mitochondrial toxins...
May 29, 2018: ELife
Ziqing Yu, Ruizhen Chen, Minghui Li, Yong Yu, Yixiu Liang, Fei Han, Shengmei Qin, Xueying Chen, Yangang Su, Junbo Ge
BACKGROUND: HF incurs high disease burden, and the effectiveness of known HF treatments is unsatisfactory. Therefore, seeking novel therapeutic target of HF is important. The present study aimed to investigate the role of the mitochondrial calcium uniporter (MCU) and its relationship with autophagy in overload-induced heart failure (HF). METHODS AND RESULTS: In both early-stage and end-stage of pressure overload-induced HF, MCU appeared up-regulated along with heart enlargement, increased microtubule-associated proteins 1A/1B light chain 3B (LC3B) II/I ratio and autophagosome content, damaged cardiac function, and ventricular asynchrony...
May 20, 2018: International Journal of Cardiology
Xiufang Chen, Long Yi, Shiyu Song, Lei Wang, Qiao Liang, Yong Wang, Yongzheng Wu, Qian Gao
AIMS: High level of saturated fatty acids leads to mitochondrial dysfunction and inflammation in the development of insulin resistance in skeletal muscle. We recently found that puerarin improved impaired insulin signaling in skeletal muscle in diabetic animals and in myotubes in vitro. However, whether puerarin can act directly on muscle cells to alleviate lipid-induced mitochondrial dysfunction and inflammation remains obscure. This study was conducted to analyze the attributive properties of puerarin against mitochondrial dysfunction and inflammation in skeletal muscle cells with insulin resistance...
May 23, 2018: Life Sciences
Anthea Di Rita, Pasquale D'Acunzo, Luca Simula, Silvia Campello, Flavie Strappazzon, Francesco Cecconi
Therapeutic strategies are needed to protect dopaminergic neurons in Parkinson's disease (PD) patients. Oxidative stress caused by dopamine may play an important role in PD pathogenesis. Selective autophagy of mitochondria (mitophagy), mainly regulated by PINK1 and PARKIN, plays an important role in the maintenance of cell homeostasis. Mutations in those genes cause accumulation of damaged mitochondria, leading to nigral degeneration and early-onset PD. AMBRA1ActA is a fusion protein specifically expressed at the mitochondria, and whose expression has been shown to induce a powerful mitophagy in mammalian cells...
2018: Frontiers in Cellular Neuroscience
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