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Christian Galasso, Genoveffa Nuzzo, Christophe Brunet, Adrianna Ianora, Angela Sardo, Angelo Fontana, Clementina Sansone
Marine dinoflagellates are a valuable source of bioactive molecules. Many species produce cytotoxic compounds and some of these compounds have also been investigated for their anticancer potential. Here, we report the first investigation of the toxic dinoflagellate Alexandrium minutum as source of water-soluble compounds with antiproliferative activity against human lung cancer cells. A multi-step enrichment of the phenol⁻water extract yielded a bioactive fraction with specific antiproliferative effect (IC50 = 0...
December 12, 2018: Marine Drugs
Åsa B Gustafsson, Gerald W Dorn
The central functions fulfilled by mitochondria as both energy generators essential for tissue homeostasis and gateways to programmed apoptotic and necrotic cell death mandate tight control over the quality and quantity of these ubiquitous endosymbiotic organelles. Mitophagy, the targeted engulfment and destruction of mitochondria by the cellular autophagy apparatus, has conventionally been considered as the mechanism primarily responsible for mitochondrial quality control. However, our understanding of how, why, and under what specific conditions mitophagy is activated has grown tremendously over the past decade...
January 1, 2019: Physiological Reviews
Prakash P Praharaj, Prajna P Naik, Debasna P Panigrahi, Chandra S Bhol, Kewal K Mahapatra, Srimanta Patra, Gautam Sethi, Sujit Kumar Bhutia
The efficacy of chemotherapy is mostly restricted by the drug resistance developed during the course of cancer treatment. Mitophagy, as a pro-survival mechanism, crucially maintains mitochondrial homeostasis and it is one of the mechanisms that cancer cells adopt for their progression. On the other hand, mitochondrial apoptosis, a precisely regulated form of cell death, acts as a tumor-suppressive mechanism by targeting cancer cells. Mitochondrial lipids, such as cardiolipin, ceramide, and sphingosine-1-phosphate, act as a mitophageal signal for the clearance of damaged mitochondria by interacting with mitophagic machinery as well as activate mitochondrial apoptosis via the release of cytochrome c into the cytoplasm...
December 11, 2018: Cellular and Molecular Life Sciences: CMLS
Dzhamilja Safiulina, Malle Kuum, Vinay Choubey, Nana Gogichaishvili, Joanna Liiv, Miriam A Hickey, Michal Cagalinec, Merle Mandel, Akbar Zeb, Mailis Liiv, Allen Kaasik
The Parkinson's disease-associated protein kinase PINK1 and ubiquitin ligase Parkin coordinate the ubiquitination of mitochondrial proteins, which marks mitochondria for degradation. Miro1, an atypical GTPase involved in mitochondrial trafficking, is one of the substrates tagged by Parkin after mitochondrial damage. Here, we demonstrate that a small pool of Parkin interacts with Miro1 before mitochondrial damage occurs. This interaction does not require PINK1, does not involve ubiquitination of Miro1 and also does not disturb Miro1 function...
November 30, 2018: EMBO Journal
Diego Grassi, Natalia Diaz-Perez, Laura A Volpicelli-Daley, Corinne Ida Lasmézas
We recently identified a truncated and phosphorylated form of α-synuclein, pα-syn*, as a key neurotoxic α-synuclein species found in cultured neurons, as well as in mouse and Parkinson's disease patients' brains. Small pα-syn* aggregates localize to mitochondria and induce mitochondrial damage and fragmentation. Herein, we investigated the molecular basis of pα-syn*-induced toxicity. By immunofluorescence, we found phosphorylated MKK4, JNK, ERK5 and p38 MAPKs in pα-syn* inclusions. pJNK colocalized with pα-syn* at mitochondria and mitochondria-associated ER membranes where it was associated with BiP and pACC1, markers for the ER and energy deprivation, respectively...
November 22, 2018: Neurobiology of Disease
Lu He, Qionglin Zhou, Zheng Huang, Jin Xu, Hong Zhou, Deguan Lv, Liqun Lu, Shifang Huang, Mingzhu Tang, Jiuchang Zhong, Jianxiong Chen, Xulin Luo, Lanfang Li, Linxi Chen
Aberrant proliferation of vascular smooth muscle cells (VSMC) is a critical contributor to the pathogenesis of atherosclerosis (AS). Our previous studies have demonstrated that apelin-13/APJ confers a proliferative response in VSMC, however, its underlying mechanism remains elusive. In this study, we aimed to investigate the role of mitophagy in apelin-13-induced VSMC proliferation and atherosclerotic lesions in apolipoprotein E knockout (ApoE-/-) mice. Apelin-13 enhances human aortic VSMC proliferation and proliferative regulator proliferating cell nuclear antigen expression in dose and time-dependent manner, while is abolished by APJ antagonist F13A...
November 19, 2018: Journal of Cellular Physiology
Ilaria Bellezza
Age-related macular degeneration is one of the leading causes of vision loss in the elderly. Genetics, environmental insults, and age-related issues are risk factors for the development of the disease. All these risk factors are linked to the induction of oxidative stress. In young subjects retinal pigment epithelial cells mitigate reactive oxygen generation by the elimination of dysfunctional mitochondria, via mitophagy, and by increasing antioxidant defenses via Nrf2 activation. The high amount of UV light absorbed by the retina, together with cigarette smoking, cooperate with the aging process to increase the amount of reactive oxygen species generated by retinal pigment epithelium where oxidative stress arises...
2018: Frontiers in Pharmacology
Roberta Coluccia, Salvatore Raffa, Danilo Ranieri, Andrea Micaloni, Sabatino Valente, Gerardo Salerno, Cristina Scrofani, Marco Testa, Giovanna Gallo, Erika Pagannone, Maria Rosaria Torrisi, Massimo Volpe, Speranza Rubattu
Oxidative stress is currently viewed as a key factor in the genesis and progression of Heart Failure (HF). The aim of this study was to characterize the mitochondrial changes linked to oxidative stress generation in circulating peripheral blood mononuclear cells isolated from chronic HF patients (HF_PBMCs) in order to highlight the involvement of mitochondrial dysfunction in the pathophysiology of HF. To assess the production of reactive oxygen species (ROS), mitochondrial function and ultrastructure and the mitophagic flux in circulating PBMCs we enrolled 15 patients with HF and a control group of ten healthy subjects...
October 12, 2018: Oncotarget
Yuho Kim, Matthew Triolo, Avigail T Erlich, David A Hood
Autophagy and mitophagy are important for training-inducible muscle adaptations, yet it remains unclear how these systems are regulated throughout the adaptation process. Here, we studied autophagic and mitophagic flux in the skeletal muscles of Sprague-Dawley rats (300-500 g) exposed to chronic contractile activity (CCA; 3 h/day, 9 V, 10 Hz continuous, 0.1 ms pulse duration) for 1, 2, 5, and 7 days (N = 6-8/group). In order to determine the flux rates, colchicine (COL; 0.4 mg/ml/kg) was injected 48 h before tissue collection, and we evaluated differences of autophagosomal protein abundances (LC3-II and p62) between colchicine- and saline-injected animals...
October 27, 2018: Pflügers Archiv: European Journal of Physiology
Xinxin Hu, Yi Dai, Rong Zhang, Kunte Shang, Xinghuai Sun
Glaucoma is a neurodegenerative disease that features progressive loss of retinal ganglion cells (RGCs). Increasing evidences have revealed that impaired mitochondrial dynamics occurs early in neurodegenerative diseases. Optic Atrophy Type 1 (OPA1), a mitochondrial fusion protein, has recently been suggested to be a mitophagic factor. Our previous studies found that glaucomatous retinal damage may be ameliorated by an increase in mitochondrial OPA1. In this study, we explored the mechanism involved in OPA1 mediated neuroprotection and its relationship with parkin dependent mitophagy in experimental glaucoma models...
2018: Frontiers in Molecular Neuroscience
L Hui, H Wu, T-W Wang, N Yang, X Guo, X-J Jang
PURPOSE: The purpose of our study was to investigate an underlying mechanism that hydrogen peroxide-induced mitophagy contributed to laryngeal cancer cells survivals under oxidative stress condition. METHODS: Tumor tissue and serum samples were collected from patients with laryngeal cancer. The Hep2 cell, a human laryngeal carcinoma cell, was used in in vitro experiments. The levels of lipid peroxidation were analyzed by ELISA. Knockdown of FUNDC1 was performed by RNAi...
October 3, 2018: Clinical & Translational Oncology
Alan Diot, Thomas Agnew, Jeremy Sanderson, Chunyan Liao, Janet Carver, Ricardo Pires das Neves, Rajeev Gupta, Yanping Guo, Caroline Waters, Sharon Seto, Matthew J Daniels, Eszter Dombi, Tiffany Lodge, Karl Morten, Suzannah A Williams, Tariq Enver, Francisco J Iborra, Marcela Votruba, Joanna Poulton
Background: Autosomal dominant optic atrophy (ADOA) is usually caused by mutations in the essential gene, OPA1. This encodes a ubiquitous protein involved in mitochondrial dynamics, hence tissue specificity is not understood. Dysregulated mitophagy (mitochondria recycling) is implicated in ADOA, being increased in OPA1 patient fibroblasts. Furthermore, autophagy may be increased in retinal ganglion cells (RGCs) of the OPA1Q285STOP mouse model. Aims: We developed a mouse model for studying mitochondrial dynamics in order to investigate mitophagy in ADOA...
2018: Frontiers in Cell and Developmental Biology
Jun Zhang, Bin Wang, Hong Wang, Hui He, Qiong Wu, Xia Qin, Xi Yang, Linmu Chen, Ge Xu, Zhiyi Yuan, Qiying Yi, Zhen Zou, Chao Yu
Copper oxide nanoparticles (CuONPs) have been widely used in the industrial and pharmaceutical fields; however, their toxicity profile is deeply concerning. Currently, nanomaterials-induced toxicity in the cardiovascular system is receiving increased attention. Our previous toxicological study found that lysosomal deposition of CuONPs triggered vascular endothelial cell death, indicating that the involvement of autophagic dysfunction was crucial for CuONPs-induced toxicity in human umbilical vein endothelial cells (HUVECs)...
September 21, 2018: Free Radical Biology & Medicine
Fabiana F Ferreira, Evelise M Nazari, Yara M R Müller
Methylmercury (MeHg) is a known neurodevelopmental toxicant, which causes changes in various structures of the central nervous system (CNS). However, ultrastructural studies of its effects on the developing CNS are still scarce. Here, we investigated the effect of MeHg on the ultrastructure of the cells in spinal cord layers. Chicken embryos at E3 were treated in ovo with 0.1 μ g MeHg/50 μ L saline solution and analyzed at E10. Then, we used transmission electron microscopy (TEM) to identify possible damage caused by MeHg to the structures and organelles of the spinal cord cells...
2018: Journal of Toxicology
Anthea Di Rita, Angelo Peschiaroli, Pasquale D Acunzo, Daniela Strobbe, Zehan Hu, Jens Gruber, Mads Nygaard, Matteo Lambrughi, Gerry Melino, Elena Papaleo, Jörn Dengjel, Said El Alaoui, Michelangelo Campanella, Volker Dötsch, Vladimir V Rogov, Flavie Strappazzon, Francesco Cecconi
The selective removal of undesired or damaged mitochondria by autophagy, known as mitophagy, is crucial for cellular homoeostasis, and prevents tumour diffusion, neurodegeneration and ageing. The pro-autophagic molecule AMBRA1 (autophagy/beclin-1 regulator-1) has been defined as a novel regulator of mitophagy in both PINK1/PARKIN-dependent and -independent systems. Here, we identified the E3 ubiquitin ligase HUWE1 as a key inducing factor in AMBRA1-mediated mitophagy, a process that takes place independently of the main mitophagy receptors...
September 14, 2018: Nature Communications
Carmen Teodorof-Diedrich, Stephen A Spector
HIV enters the central nervous system (CNS) during the early stages of infection and can cause neurological dysfunction, including neurodegeneration and neurocognitive impairment. The specific autophagy responsible for removal of damaged mitochondria (mitophagy) and mitochondrial dynamics constitute neuronal mitochondrial quality control mechanisms and are impaired in neurodegenerative disorders and numerous other diseases. The release of HIV proteins gp120 and Tat from infected cells is thought to play an important role in HIV-associated neurocognitive disorders (HAND), but the mechanism(s) leading to impairment are poorly understood...
November 15, 2018: Journal of Virology
Yang Yuan, Shan-Shan Pan, Dong-Feng Wan, Jiao Lu, Yue Huang
Previous studies have shown that early exercise preconditioning (EEP) imparts a protective effect on acute cardiovascular stress. However, how mitophagy participates in exercise preconditioning- (EP-) induced cardioprotection remains unclear. EEP may involve mitochondrial protection, which presumably crosstalks with predominant H2 O2 oxidative stress. Our EEP protocol involves four periods of 10 min running with 10 min recovery intervals. We added a period of exhaustive running and a pretreatment using phosphoinositide 3-kinase (PI3K)/autophagy inhibitor wortmannin to test this protective effect...
2018: Oxidative Medicine and Cellular Longevity
Zhanwei Zhang, Jianbai Yu
Mitochondrial dysfunction has been acknowledged as the key pathogenic mechanism in cerebral ischemia-reperfusion (IR) injury. Mitophagy is the protective system used to sustain mitochondrial homeostasis. However, the upstream regulator of mitophagy in response to brain IR injury is not completely understood. Nuclear receptor subfamily 4 group A member 1 (NR4A1) has been found to be associated with mitochondrial protection in a number of diseases. The aim of our study is to explore the functional role of NR4A1 in cerebral IR injury, with a particular focus on its influence on mitophagy...
October 2018: Neurochemical Research
Ana C Bento, Claudia C Bippes, Corina Kohler, Charles Hemion, Stephan Frank, Albert Neutzner
Clearance of damaged mitochondria through mitophagy is critical for maintaining mitochondrial fidelity and the prevention of neurodegeneration. Here, we report on the UBX domain-containing, p97/VCP cofactor UBXD1/UBXN6/UBXDC2 and its role in mitophagy. Recognizing depolarized mitochondria via its C-terminal UBX domain, UBXD1 translocates to mitochondria in a Parkin-dependent manner. During Parkin-independent mitophagy, UBXD1 shows no mitochondrial translocation. Once translocated, UBXD1 recruits p97 to mitochondria via a bipartite binding motif consisting of its N-terminal VIM and PUB domains...
August 17, 2018: Scientific Reports
Ching-Chi Chiu, Chin-Song Lu, Yi-Hsin Weng, Ying-Ling Chen, Ying-Zu Huang, Rou-Shayn Chen, Yi-Chuan Cheng, Yin-Cheng Huang, Yu-Chuan Liu, Szu-Chia Lai, Kun-Jun Lin, Yan-Wei Lin, Yu-Jie Chen, Chao-Lang Chen, Tu-Hsueh Yeh, Hung-Li Wang
PARK14 patients with homozygous (D331Y) PLA2G6 mutation display motor deficits of pure early-onset Parkinson's disease (PD). The aim of this study is to investigate the pathogenic mechanism of mutant (D331Y) PLA2G6-induced PD. We generated knockin (KI) mouse model of PARK14 harboring homozygous (D331Y) PLA2G6 mutation. Then, we investigated neuropathological and neurological phenotypes of PLA2G6D331Y/D331Y KI mice and molecular pathogenic mechanisms of (D331Y) PLA2G6-induced degeneration of substantia nigra (SN) dopaminergic neurons...
August 8, 2018: Molecular Neurobiology
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