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Mitochondrial permeability transition pore

Salvatore Nesci
The molecular structure of the transmembrane domain of ATP synthases is responsible for the inner mitochondrial membrane bending. According to the hypothesized mechanism, ATP synthase dissociation from dimers to monomers, triggered by Ca2+ binding to F1 , allows the mitochondrial permeability transition pore formation at the interface between the detached monomers.
March 16, 2018: Trends in Biochemical Sciences
Toshiyuki Yano, Koki Abe, Masaya Tanno, Takayuki Miki, Atsushi Kuno, Tetsuji Miura, Charles Steenbergen
p53 is well known as a regulator of apoptosis and autophagy. In addition, a recent study showed that p53 is a modulator of the opening of the mitochondrial permeability transition pore (mPTP), a trigger event of necrosis, but the role of p53 in necrosis induced by myocardial ischemia-reperfusion (I/R) remains unclear. The aim of this study was to determine the role of p53 in acute myocardial I/R injury in perfused mouse hearts. In male C57BL6 mice between 12 and 15 weeks of age, 2 types of p53 inhibitors were used to suppress p53 function during I/R: pifithrin-α, an inhibitor of transcriptional functions of p53, and pifithrin-μ, an inhibitor of p53 translocation from the cytosol to mitochondria...
January 1, 2018: Journal of Cardiovascular Pharmacology and Therapeutics
Suzanne R Burstein, Hyun Jeong Kim, Jasmine A Fels, Liping Qian, Sheng Zhang, Ping Zhou, Anatoly A Starkov, Costantino Iadecola, Giovanni Manfredi
Recent evidence highlights a role for sex and hormonal status in regulating cellular responses to ischemic brain injury and neurodegeneration. A key pathological event in ischemic brain injury is the opening of a mitochondrial permeability transition pore (MPT) induced by excitotoxic calcium levels, which can trigger irreversible damage to mitochondria accompanied by the release of pro-apoptotic factors. However, sex differences in brain MPT modulation have not yet been explored. Here, we show that mitochondria isolated from female mouse forebrain have a lower calcium threshold for MPT than male mitochondria, and that this sex difference depends on the MPT regulator cyclophilin D (CypD)...
March 14, 2018: Biochimica et Biophysica Acta
Pan Pan, Hongmin Zhang, Longxiang Su, Xiaoting Wang, Dawei Liu
To explore the mechanism of mitochondrial uncoupling protein 2 (UCP2) mediating the protective of melatonin when septic cardiomyopathy. UCP2 knocked out mice and cardiomyocytes were used to study the effect of melatonin in response to LPS. Indicators of myocardial and mitochondria injury including mitochondrial membrane potential, mitochondrial permeability transition pore, calcium loading, ROS, and ATP detection were assessed. In addition cell viability and apoptosis as well as autophagy-associated proteins were evaluated...
March 16, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Danh T Tran, Scott Esckilsen, Jennifer Mulligan, Shikhar Mehrotra, Carl Atkinson, Satish N Nadig
BACKGROUND: Microvascular endothelial cells (ECs) are central to an allograft's immunogenicity. Cold ischemia and reperfusion injury associated with static cold storage and warm reperfusion activates ECs and increases the immunogenicity of the allograft. Following reperfusion, mitochondrial permeability transition pore (mPTP) opening contributes to mitochondrial dysfunction in the allograft, which correlates to alloimmune rejection. Current understanding of this relationship, however, centers on the whole allograft instead of ECs...
March 10, 2018: Transplantation
Debika Datta, Preeti Khatri, Ambika Singh, Dhira Rani Saha, Gaurav Verma, Rajagopal Raman, Shibnath Mazumder
Mycobacterium fortuitum is a natural fish pathogen. It induces apoptosis in headkidney macrophages (HKM) of catfish, Clarias sp though the mechanism remains largely unknown. We observed M. fortuitum triggers calcium (Ca2+ ) insult in the sub-cellular compartments which elicits pro-apototic ER-stress factor CHOP. Alleviating ER-stress inhibited CHOP and attenuated HKM apoptosis implicating ER-stress in the pathogenesis of M. fortuitum . ER-stress promoted calpain activation and silencing the protease inhibited caspase-12 activation...
December 2018: Cell Death Discovery
Kilmer S McCully
The indoleamine hormone melatonin is synthesized by the pineal gland, controls circadian rhythm, and is dependent upon adenosyl methionine for enzymatic synthesis of melatonin from N-acetyl serotonin. Pineal melatonin secretion declines dramatically with aging and dementia. Elevated plasma homocysteine is a risk factor for atherosclerosis and Alzheimer's disease, and the marked decline in adenosyl methionine with aging leads to dysregulation of methionine metabolism and hyperhomocysteinemia. Thioretinaco ozonide is a disulfonium complex formed from thioretinamide, cobalamin, and ozone, which binds the alpha and gamma-phosphate groups of adenosine triphosphate (ATP) and oxygen in the process of oxidative phosphorylation within mitochondria...
January 2018: Annals of Clinical and Laboratory Science
Xu Chen, Xuan Li, Wenyan Zhang, Jie He, Bo Xu, Bin Lei, Zhenhua Wang, Courtney Cates, Thomas Rousselle, Ji Li
BACKGROUND: AMP-activated Protein Kinase (AMPK) is a stress-activated kinase that protects against cardiomyocyte injury during ischemia and reperfusion. c-Jun N-terminal kinase (JNK), a mitogen activated protein kinase, is activated by ischemia and reperfusion. NF-κB is an important transcription factor involved in ischemia and reperfusion injury. METHODS AND RESULTS: The intrinsic activation of AMPK attenuates the inflammation which occurred during ischemia/reperfusion through the modulation of the JNK mediated NF-κB signaling pathway...
March 8, 2018: Metabolism: Clinical and Experimental
Vachirapong Sompakdee, Auemduan Prawan, Laddawan Senggunprai, Upa Kukongviriyapan, Papavee Samathiwat, Jaroon Wandee, Veerapol Kukongviriyapan
AIMS: Transcription factor Nrf2, which regulates the expression of cytoprotective and antioxidant enzymes, contributes to proliferation and resistance to chemotherapy in cancer. The inhibition of Nrf2 can sensitize cholangiocarcinoma (CCA) cells to the cytotoxicity of several chemotherapeutic agents. In this study, we investigated the mechanism of this chemosensitizing effect. MAIN METHODS: KKU-100 cells were used in the study. Nrf2 expression was knocked down by siRNA and expression was validated by reverse transcription and polymerase chain reaction...
March 5, 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
José Teixeira, Catarina Oliveira, Fernando Cagide, Ricardo Amorim, Jorge Garrido, Fernanda Borges, Paulo J Oliveira
Pharmacological interventions targeting mitochondria present several barriers for a complete efficacy. Therefore, a new mitochondriotropic antioxidant (AntiOxBEN3 ) based on the dietary antioxidant gallic acid was developed. AntiOxBEN3 accumulated several thousand-fold inside isolated rat liver mitochondria, without causing disruption of the oxidative phosphorylation apparatus, as seen by the unchanged respiratory control ratio, phosphorylation efficiency, and transmembrane electric potential. AntiOxBEN3 showed also limited toxicity on human hepatocarcinoma cells...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Wajihah Mughal, Matthew Martens, Jared Field, Donald Chapman, Jianhe Huang, Sunil Rattan, Yan Hai, Kyle G Cheung, Stephanie Kereliuk, Adrian R West, Laura K Cole, Grant M Hatch, William Diehl-Jones, Richard Keijzer, Vernon W Dolinsky, Ian M Dixon, Michael S Parmacek, Joseph W Gordon
Myocardin is a transcriptional co-activator required for cardiovascular development, but also promotes cardiomyocyte survival through an unclear molecular mechanism. Mitochondrial permeability transition is implicated in necrosis, while pore closure is required for mitochondrial maturation during cardiac development. We show that loss of myocardin function leads to subendocardial necrosis at E9.5, concurrent with elevated expression of the death gene Nix. Mechanistically, we demonstrate that myocardin knockdown reduces microRNA-133a levels to allow Nix accumulation, leading to mitochondrial permeability transition, reduced mitochondrial respiration, and necrosis...
March 6, 2018: Cell Death and Differentiation
Hannah J Whittington, Philip J Ostrowski, Debra J McAndrew, Fang Cao, Andrew Shaw, Thomas R Eykyn, Hannah Lake, Jack Tyler, Jurgen E Schneider, Stefan Neubauer, Sevasti Zervou, Craig A Lygate
Aims: Mitochondrial creatine kinase (MtCK) couples ATP production via oxidative phosphorylation to phosphocreatine in the cytosol, which acts as a mobile energy store available for regeneration of ATP at times of high demand. We hypothesised that elevating MtCK would be beneficial in ischaemia-reperfusion (I/R) injury. Methods and Results: Mice were created overexpressing the sarcomeric MtCK gene with αMHC promoter at the Rosa26 locus (MtCK-OE) and compared with wild-type (WT) littermates...
March 2, 2018: Cardiovascular Research
Carola Stockburger, Schamim Eckert, Gunter P Eckert, Kristina Friedland-Leuner, Walter E Müller
Because of the failure of all amyloid-β directed treatment strategies for Alzheimer's disease (AD), the concept of mitochondrial dysfunction as a major pathomechanism of the cognitive decline in aging and AD has received substantial support. Accordingly, improving mitochondrial function as an alternative strategy for new drug development became of increasing interest and many different compounds have been identified which improve mitochondrial function in preclinical in vitro and in vivo experiments. However, very few if any have been investigated in clinical trials, representing a major drawback of the mitochondria directed drug development...
February 28, 2018: Journal of Alzheimer's Disease: JAD
Pingjun Zhu, Shunying Hu, Qinhua Jin, Dandan Li, Feng Tian, Sam Toan, Yang Li, Hao Zhou, Yundai Chen
Receptor-interacting protein 3 (Ripk3)-mediated necroptosis contributes to cardiac ischaemia-reperfusion (IR) injury through poorly defined mechanisms. Our results demonstrated that Ripk3 was strongly upregulated in murine hearts subjected to IR injury and cardiomyocytes treated with LPS and H2 O2 . The higher level of Ripk3 was positively correlated to the infarction area expansion, cardiac dysfunction and augmented cardiomyocytes necroptosis. Function study further illustrated that upregulated Ripk3 evoked the endoplasmic reticulum (ER) stress, which was accompanied with an increase in intracellular Ca2+ level ([Ca2+ ]c) and xanthine oxidase (XO) expression...
March 1, 2018: Redox Biology
Qi-Wei Huang, Na-Na Zhai, Tao Huang, Dao-Ming Li
The aim of this study was to investigate the effects of hirsutine on apoptosis of breast cancer cells and its possible mechanism. The MCF-10A, MCF-7 and MDA-MB-231 cells were treated with hirsutine at different concentrations for 48 h or incubated with 160 μmol/L hirsutine for 24, 48, and 72 h. The MCF-10A cell line is a non-tumorigenic epithelial cell line, and the MCF-7 and MDA-MB-231 are human breast adenocarcinoma cell lines. CCK-8 assay was employed to detect the cell viability. Flow cytometry was used to assay the apoptosis and mitochondrial membrane potential (MMP)...
February 25, 2018: Sheng Li Xue Bao: [Acta Physiologica Sinica]
Hye-Sang Park, Chang-Ju Kim, Hyo-Bum Kwak, Mi-Hyun No, Jun-Won Heo, Tae-Woon Kim
Although chemotherapy increases the survival rate of patients with various cancers, such treatment can induce acute or long-term cognitive dysfunction a phenomenon known as post-chemotherapy cognitive impairment (PCCI) or "chemobrain." Exercise is known to positively affect brain function. Thus, the present study aimed to determine whether symptoms of chemobrain and disruptions in the neuroplasticity and functioning of hippocampal mitochondria can be prevented or relieved by exercise. Wistar rats were separated into the following groups: control, control plus exercise, chemobrain, and chemobrain plus exercise...
February 22, 2018: Neuropharmacology
Cristiane Cecatto, Alexandre Umpierrez Amaral, Janaína Camacho da Silva, Alessandro Wajner, Mariana de Oliveira Vargas Schimit, Lucas Henrique Rodrigues da Silva, Simone Magagnin Wajner, Ângela Zanatta, Roger Frigério Castilho, Moacir Wajner
We studied the effects of the major long-chain fatty acids accumulating in very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency, namely cis-5-tetradecenoic acid (Cis-5) and myristic acid (Myr), on important mitochondrial functions in isolated mitochondria from heart, cardiac fibers of juvenile rats and cardiomyocytes. Cis-5 and Myr at pathological concentrations markedly reduced mitochondrial membrane potential (ΔΨm), matrix NAD(P)H pool, Ca2+ retention capacity, ADP- (state 3) and CCCP-stimulated (uncoupled) respiration and ATP generation...
February 24, 2018: FEBS Journal
Zhantu Liu, Lili Yang, Jiyi Huang, Ping Xu, Zeyu Zhang, Dong Yin, Jichun Liu, Huan He, Ming He
Ischemia/reperfusion (I/R) injury is the major cause of acute cardiovascular disease worldwide. 14-3-3η protein has been demonstrated to protect myocardium against I/R injury. Luteoloside (Lut), a flavonoid found in many Chinese herbs, exerts myocardial protection effects. However, the mechanism remains unclear. We hypothesize that the cardioprotective role of Lut is exerted by regulating the 14-3-3η signal pathway. To investigate our hypothesis, an in vitro I/R model was generated in H9C2 cardiomyocytes by anoxia/reoxygenation (A/R) treatment...
February 21, 2018: Phytotherapy Research: PTR
Soni Deshwal, Marleen Forkink, Chou-Hui Hu, Guido Buonincontri, Salvatore Antonucci, Moises Di Sante, Michael P Murphy, Nazareno Paolocci, Daria Mochly-Rosen, Thomas Krieg, Fabio Di Lisa, Nina Kaludercic
Monoamine oxidase (MAO) inhibitors ameliorate contractile function in diabetic animals, but the mechanisms remain unknown. Equally elusive is the interplay between the cardiomyocyte alterations induced by hyperglycemia and the accompanying inflammation. Here we show that exposure of primary cardiomyocytes to high glucose and pro-inflammatory stimuli leads to MAO-dependent increase in reactive oxygen species that causes permeability transition pore opening and mitochondrial dysfunction. These events occur upstream of endoplasmic reticulum (ER) stress and are abolished by the MAO inhibitor pargyline, highlighting the role of these flavoenzymes in the ER/mitochondria cross-talk...
February 19, 2018: Cell Death and Differentiation
Peng Zhang, Chunxiao Hu, Yongyong Li, Ying Wang, Lei Gao, Kai Lu, Guanglei Chang, Yong Li, Shu Qin, Dongying Zhang
The Wnt/JNK pathway, responsible for tissue polarity in cardiogenesis in vertebrates, has been shown to play numerous roles during differentiation and development of cardiac myocytes. Van Gogh-like-2 (Vangl2) is a core component that regulates the induction of polarized cellular and tissue morphology during animal development. However, little is known about Wnt/JNK signaling pathway in the process of myocardial remodeling. In present study, we found that activation of Wnt/JNK signaling by Wnt5a stimulates enlargement of cardiomyocyte surface area...
February 15, 2018: Experimental Cell Research
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