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Mitochondria AND mTOR

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https://www.readbyqxmd.com/read/28333151/fto-is-required-for-myogenesis-by-positively-regulating-mtor-pgc-1%C3%AE-pathway-mediated-mitochondria-biogenesis
#1
Xiaobo Wang, Ning Huang, Min Yang, Dandan Wei, Haoran Tai, Xiaojuan Han, Hui Gong, Jiao Zhou, Jianqiong Qin, Xiawei Wei, Honghan Chen, Tingting Fang, Hengyi Xiao
Global germ line loss of fat mass- and obesity-associated (FTO) gene results in both the reduction of fat mass and lean mass in mice. The role of FTO in adipogenesis has been proposed, however, that in myogenesis has not. Skeletal muscle is the main component of body lean mass, so its connection with FTO physiologic significance need to be clarified. Here, we assessed the impact of FTO on murine skeletal muscle differentiation by in vitro and in vivo experiments. We found that FTO expression increased during myoblasts differentiation, while the silence of FTO inhibited the differentiation; in addition, skeletal muscle development was impaired in skeletal muscle FTO-deficient mice...
March 23, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28283188/targeted-cytoplasmic-irradiation-and-autophagy
#2
Jinhua Wu, Bo Zhang, Yen-Ruh Wuu, Mercy M Davidson, Tom K Hei
The effect of ionizing irradiation on cytoplasmic organelles is often underestimated because the general dogma considers direct DNA damage in the nuclei to be the primary cause of radiation induced toxicity. Using a precision microbeam irradiator, we examined the changes in mitochondrial dynamics and functions triggered by targeted cytoplasmic irradiation with α-particles. Mitochondrial dysfunction induced by targeted cytoplasmic irradiation led to activation of autophagy, which degraded dysfunctional mitochondria in order to maintain cellular energy homeostasis...
March 1, 2017: Mutation Research
https://www.readbyqxmd.com/read/28238805/pharmacological-inhibition-of-lsd1-and-mtor-reduces-mitochondrial-retention-and-associated-ros-levels-in-the-red-blood-cells-of-sickle-cell-disease
#3
Ramasamy Jagadeeswaran, Benjamin A Vazquez, Muthusamy Thiruppathi, Balaji B Ganesh, Vinzon Ibanez, Shuaiying Cui, James D Engel, Alan M Diamond, Robert E Molokie, Joseph DeSimone, Donald Lavelle, Angela Rivers
Sickle cell disease (SCD), an inherited blood disorder caused by a point mutation that renders hemoglobin susceptible to polymerization when deoxygenated, affects millions of people worldwide. Manifestations of SCD include chronic hemolytic anemia, inflammation, painful vaso-occlusive crises, multisystem organ damage, and reduced life expectancy. Part of SCD pathophysiology is the excessive formation of intracellular reactive oxygen species (ROS) in SCD red blood cells (RBCs) which accelerates their hemolysis...
February 23, 2017: Experimental Hematology
https://www.readbyqxmd.com/read/28230361/10-gingerol-a-phytochemical-derivative-from-tongling-white-ginger-inhibits-cervical-cancer-insights-into-the-molecular-mechanism-and-inhibitory-targets
#4
Fang Zhang, Kiran Thakur, Fei Hu, Jian-Guo Zhang, Zhao-Jun Wei
With the aim of evaluating anticancerous activities of 10-gingerol (10-G) against HeLa cells, it was purified and identified from "Tongling white ginger" by HSCCC, UPLC-TOF-MS/MS, and NMR analysis, respectively. 10-G inhibited the proliferation of HeLa cells at IC50 (29.19 μM) and IC80 (50.87 μM) with altered cell morphology, increased cytotoxicity, and arrested cell cycle in the G0/G1 phase. Most cell cycle related genes and protein expression significantly decreased, followed by a slight decrease in a few without affecting cyclin B1 and cyclin E1 (protein)...
March 1, 2017: Journal of Agricultural and Food Chemistry
https://www.readbyqxmd.com/read/28187451/gsk1059615-kills-head-and-neck-squamous-cell-carcinoma-cells-possibly-via-activating-mitochondrial-programmed-necrosis-pathway
#5
Jing Xie, Quan Li, Xi Ding, Yunyun Gao
This study tested the anti-head and neck squamous cell carcinoma (HNSCC) cell activity by GSK1059615, a novel PI3K and mTOR dual inhibitor. GSK1059615 inhibited survival and proliferation of established (SCC-9, SQ20B and A253 lines) and primary human HNSCC cells. GSK1059615 blocked PI3K-AKT-mTOR activation in HNSCC cells. Intriguingly, GSK1059615 treatment in HNSCC cells failed to provoke apoptosis, but induced programmed necrosis. The latter was tested by mitochondria depolarization, ANT-1-cyclophilin-D mitochondrial association and lactate dehydrogenase (LDH) release...
February 7, 2017: Oncotarget
https://www.readbyqxmd.com/read/28161619/combination-of-metformin-with-chemotherapeutic-drugs-via-different-molecular-mechanisms
#6
REVIEW
Mei Peng, Kwame Oteng Darko, Ting Tao, Yanjun Huang, Qiongli Su, Caimei He, Tao Yin, Zhaoqian Liu, Xiaoping Yang
Metformin, a widely prescribed drug for treating type II diabetes, is one of the most extensively recognized metabolic modulators which has shown an important anti-cancer property. However, fairly amount of clinical trials on its single administration have not demonstrated a convincing efficiency yet. Thus, recent studies tend to combine metformin with clinical commonly used chemotherapeutic drugs to decrease their toxicity and attenuate their tumor resistance. These strategies have displayed promising clinical benefits...
March 2017: Cancer Treatment Reviews
https://www.readbyqxmd.com/read/28161373/post-onset-oral-rapamycin-treatment-delays-development-of-mitochondrial-encephalopathy-only-at-supramaximal-doses
#7
Roberta Felici, Daniela Buonvicino, Mirko Muzzi, Leonardo Cavone, Daniele Guasti, Andrea Lapucci, Sara Pratesi, Francesco De Cesaris, Francesca Luceri, Alberto Chiarugi
Mitochondrial encephalopathies are fatal, infantile neurodegenerative disorders caused by a deficit of mitochondrial functioning, for which there is urgent need to identify efficacious pharmacological treatments. Recent evidence shows that rapamycin administered both intraperitoneally or in the diet delays disease onset and enhances survival in the Ndufs4 null mouse model of mitochondrial encephalopathy. To delineate the clinical translatability of rapamycin in treatment of mitochondrial encephalopathy, we evaluated the drug's effects on disease evolution and mitochondrial parameters adopting treatment paradigms with fixed daily, oral doses starting at symptom onset in Ndufs4 knockout mice...
February 1, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28143890/localization-of-mtorc2-activity-inside-cells
#8
Michael Ebner, Benjamin Sinkovics, Magdalena Szczygieł, Daniela Wolfschoon Ribeiro, Ivan Yudushkin
Activation of protein kinase Akt via its direct phosphorylation by mammalian target of rapamycin (mTOR) complex 2 (mTORC2) couples extracellular growth and survival cues with pathways controlling cell growth and proliferation, yet how growth factors target the activity of mTORC2 toward Akt is unknown. In this study, we examine the localization of the obligate mTORC2 component, mSin1, inside cells and report the development of a reporter to examine intracellular localization and regulation by growth factors of the endogenous mTORC2 activity...
February 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/28135838/novel-role-of-the-mitochondrial-protein-fus1-in-protection-from-premature-hearing-loss-via-regulation-of-oxidative-stress-and-nutrient-and-energy-sensing-pathways-in-the-inner-ear
#9
Winston J T Tan, Lei Song, Morven Graham, Amy Schettino, Dhasakumar Navaratnam, Wendell G Yarbrough, Joseph Santos-Sacchi, Alla V Ivanova
AIMS: Acquired hearing loss is a worldwide epidemic that affects all ages. It is multifactorial in etiology with poorly characterized molecular mechanisms. Mitochondria are critical components in hearing. Here, we aimed to identify the mechanisms of mitochondria-dependent hearing loss using Fus1 KO mice, our novel model of mitochondrial dysfunction/oxidative stress. RESULTS: Using auditory brainstem responses (ABRs), we characterized the Fus1 KO mouse as a novel, clinically relevant model of age-related hearing loss (ARHL) of metabolic etiology...
March 9, 2017: Antioxidants & Redox Signaling
https://www.readbyqxmd.com/read/28121223/using-tuberous-sclerosis-complex-to-understand-the-impact-of-mtorc1-signaling-on-mitochondrial-dynamics-and-mitophagy-in-neurons
#10
Darius Ebrahimi-Fakhari, Afshin Saffari, Lara Wahlster, Mustafa Sahin
Constitutive activation of the MTOR pathway is a key feature of defects in the tuberous sclerosis complex and other genetic neurodevelopmental diseases, collectively referred to as MTORopathies. MTORC1 hyperactivity promotes anabolic cell functions such as protein synthesis, yet at the same time catabolic processes such as macroautophagy/autophagy are suppressed. Mitochondria are major substrates of autophagy; however, their role in MTORopathies remains largely undefined. Here, we review our recent study showing that several aspects of mitochondrial function, dynamics and turnover are critically impaired in neuronal models of TSC...
January 25, 2017: Autophagy
https://www.readbyqxmd.com/read/28108310/autophagic-dysregulation-in-doxorubicin-cardiomyopathy
#11
REVIEW
Jordan J Bartlett, Purvi C Trivedi, Thomas Pulinilkunnil
Doxorubicin (DOX)-induced cardiotoxicity has been a well-known phenomenon to clinicians and scientists for decades; however, molecular mechanisms underlying DOX cardiotoxicity are still being uncovered. Although the majority of prior research have implicated nuclear and mitochondrial events to be an important etiological aspects of DOX cardiomyopathy, recent discoveries in autophagy have highlighted the renewed interest in the role of lysosome in DOX cardiomyopathy. Indeed, dysregulation of lysosomal autophagy is observed in pre-clinical models of DOX cardiotoxicity...
January 17, 2017: Journal of Molecular and Cellular Cardiology
https://www.readbyqxmd.com/read/28107184/tunneling-nanotubes-promote-intercellular-mitochondria-transfer-followed-by-increased-invasiveness-in-bladder-cancer-cells
#12
Jinjin Lu, Xiufen Zheng, Fan Li, Yang Yu, Zhong Chen, Zheng Liu, Zhihua Wang, Hua Xu, Weimin Yang
Intercellular transfer of organelles via tunneling nanotubes (TNTs) is a novel means of cell-to-cell communication. Here we demonstrate the existence of TNTs between co-cultured RT4 and T24 bladder cancer cells using light microscopy, fluorescence imaging, and scanning electron microscopy (SEM). Spontaneous unidirectional transfer of mitochondria from T24 to RT4 cells was detected using fluorescence imaging and flow cytometry. The distribution of mitochondria migrated from T24 cells was in good agreement with the original mitochondria in RT4 cells, which may imply mitochondrial fusion...
January 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/28091556/vegf-b-promotes-recovery-of-corneal-innervations-and-trophic-functions-in-diabetic-mice
#13
Guohu Di, Xiaowen Zhao, Xia Qi, Songmei Zhang, Lu Feng, Weiyun Shi, Qingjun Zhou
Vascular endothelial growth factor (VEGF)-B possesses the capacity of promoting injured peripheral nerve regeneration and restore their sensory and trophic functions. However, the contribution and mechanism of VEGF-B in diabetic peripheral neuropathy remains unclear. In the present study, we investigated the expression and role of VEGF-B in diabetic corneal neuropathy by using type 1 diabetic mice and cultured trigeminal ganglion (TG) neurons. Hyperglycemia attenuated the endogenous expression of VEGF-B in regenerated diabetic corneal epithelium, but not that of VEGF receptors in diabetic TG neurons and axons...
January 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28089725/high-concentration-of-branched-chain-amino-acids-promotes-oxidative-stress-inflammation-and-migration-of-human-peripheral-blood-mononuclear-cells-via-mtorc1-activation
#14
Olha Zhenyukh, Esther Civantos, Marta Ruiz-Ortega, Maria Soledad Sánchez, Clotilde Vázquez, Concepción Peiró, Jesús Egido, Sebastián Mas
Leucine, isoleucine and valine are essential aminoacids termed branched-chain amino acids (BCAA) due to its aliphatic side-chain. In several pathological and physiological conditions increased BCAA plasma concentrations have been described. Elevated BCAA levels predict insulin resistance development. Moreover, BCAA levels higher than 2mmol/L are neurotoxic by inducing microglial activation in maple syrup urine disease. However, there are no studies about the direct effects of BCAA in circulating cells. We have explored whether BCAA could promote oxidative stress and pro-inflammatory status in peripheral blood mononuclear cells (PBMCs) obtained from healthy donors...
March 2017: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/28078787/targeting-nasopharyngeal-carcinoma-by-artesunate-through-inhibiting-akt-mtor-and-inducing-oxidative-stress
#15
Qin Li, Wei Ni, Zhifeng Deng, Minghe Liu, Lazhi She, Qiong Xie
Drug repurposing has become an alternative therapeutic strategy for cancer treatment given the known pharmacokinetics and toxicity. The inhibitory effects of artesunate have been reported in various cancers. In this work, we investigated the effects of artesunate in nasopharyngeal carcinoma (NPC). We demonstrate that artesunate significantly inhibits proliferation via arresting NPC cells at G2/M phase. It also induces apoptosis through caspase-dependent and mitochondria-independent pathways in multiple NPC cell lines...
January 11, 2017: Fundamental & Clinical Pharmacology
https://www.readbyqxmd.com/read/28017472/loss-of-nardilysin-a-mitochondrial-co-chaperone-for-%C3%AE-ketoglutarate-dehydrogenase-promotes-mtorc1-activation-and-neurodegeneration
#16
Wan Hee Yoon, Hector Sandoval, Sonal Nagarkar-Jaiswal, Manish Jaiswal, Shinya Yamamoto, Nele A Haelterman, Nagireddy Putluri, Vasanta Putluri, Arun Sreekumar, Tulay Tos, Ayse Aksoy, Taraka Donti, Brett H Graham, Mikiko Ohno, Eiichiro Nishi, Jill Hunter, Donna M Muzny, Jason Carmichael, Joseph Shen, Valerie A Arboleda, Stanley F Nelson, Michael F Wangler, Ender Karaca, James R Lupski, Hugo J Bellen
We previously identified mutations in Nardilysin (dNrd1) in a forward genetic screen designed to isolate genes whose loss causes neurodegeneration in Drosophila photoreceptor neurons. Here we show that NRD1 is localized to mitochondria, where it recruits mitochondrial chaperones and assists in the folding of α-ketoglutarate dehydrogenase (OGDH), a rate-limiting enzyme in the Krebs cycle. Loss of Nrd1 or Ogdh leads to an increase in α-ketoglutarate, a substrate for OGDH, which in turn leads to mTORC1 activation and a subsequent reduction in autophagy...
January 4, 2017: Neuron
https://www.readbyqxmd.com/read/28009285/anabolism-associated-mitochondrial-stasis-driving-lymphocyte-differentiation-over-self-renewal
#17
William C Adams, Yen-Hua Chen, Radomir Kratchmarov, Bonnie Yen, Simone A Nish, Wen-Hsuan W Lin, Nyanza J Rothman, Larry L Luchsinger, Ulf Klein, Meinrad Busslinger, Jeffrey C Rathmell, Hans-Willem Snoeck, Steven L Reiner
Regeneration requires related cells to diverge in fate. We show that activated lymphocytes yield sibling cells with unequal elimination of aged mitochondria. Disparate mitochondrial clearance impacts cell fate and reflects larger constellations of opposing metabolic states. Differentiation driven by an anabolic constellation of PI3K/mTOR activation, aerobic glycolysis, inhibited autophagy, mitochondrial stasis, and ROS production is balanced with self-renewal maintained by a catabolic constellation of AMPK activation, mitochondrial elimination, oxidative metabolism, and maintenance of FoxO1 activity...
December 20, 2016: Cell Reports
https://www.readbyqxmd.com/read/28004006/the-different-effects-of-atorvastatin-and-pravastatin-on-cell-death-and-parp-activity-in-pancreatic-nit-1-cells
#18
Ya-Hui Chen, Yi-Chun Chen, Chin-San Liu, Ming-Chia Hsieh
Statins have been widely used drugs for lowering low-density lipoprotein and for preventing heart attack and stroke. However, the increased risk for developing diabetes during extended stain use and the molecular mechanisms remain unclear. The objective of this study was to elucidate the signaling pathway and biological function between necrosis and autophagy induced by atorvastatin (AS) and pravastatin (PS). Here we observed that atorvastatin (AS) can increase intracellular reactive oxygen species (ROS) and induce necrotic cell death and autophagy in NIT-1 cells, whereas pravastatin (PS) does not cause ROS and cell death but also induces autophagy...
2016: Journal of Diabetes Research
https://www.readbyqxmd.com/read/27993601/mitochondrial-activity-and-dynamics-changes-regarding-metabolism-in-ageing-and-obesity
#19
REVIEW
Guillermo López-Lluch
Mitochondria play an essential role in ageing and longevity. During ageing, a general deregulation of metabolism occurs, affecting molecular, cellular and physiological activities in the organism. Dysfunction of mitochondria has been associated with ageing and age-related diseases indicating their importance in the maintenance of cell homeostasis. Three major nutritional sensors, mTOR, AMPK and Sirtuins are involved in the control of mitochondrial physiology. These nutritional sensors control mitochondrial biogenesis, dynamics by regulating fusion and fission processes, and turnover through mito- and autophagy...
December 16, 2016: Mechanisms of Ageing and Development
https://www.readbyqxmd.com/read/27974663/pik3ca-mutations-enable-targeting-of-a-breast-tumor-dependency-through-mtor-mediated-mcl-1-translation
#20
Grace R Anderson, Suzanne E Wardell, Merve Cakir, Lorin Crawford, Jim C Leeds, Daniel P Nussbaum, Pallavi S Shankar, Ryan S Soderquist, Elizabeth M Stein, Jennifer P Tingley, Peter S Winter, Elizabeth K Zieser-Misenheimer, Holly M Alley, Alexander Yllanes, Victoria Haney, Kimberly L Blackwell, Shannon J McCall, Donald P McDonnell, Kris C Wood
Therapies that efficiently induce apoptosis are likely to be required for durable clinical responses in patients with solid tumors. Using a pharmacological screening approach, we discovered that combined inhibition of B cell lymphoma-extra large (BCL-XL) and the mammalian target of rapamycin (mTOR)/4E-BP axis results in selective and synergistic induction of apoptosis in cellular and animal models of PIK3CA mutant breast cancers, including triple-negative tumors. Mechanistically, inhibition of mTOR/4E-BP suppresses myeloid cell leukemia-1 (MCL-1) protein translation only in PIK3CA mutant tumors, creating a synthetic dependence on BCL-XL This dual dependence on BCL-XL and MCL-1, but not on BCL-2, appears to be a fundamental property of diverse breast cancer cell lines, xenografts, and patient-derived tumors that is independent of the molecular subtype or PIK3CA mutational status...
December 14, 2016: Science Translational Medicine
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