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Delphine Duteil, Milica Tosic, Franziska Lausecker, Hatice Z Nenseth, Judith M Müller, Sylvia Urban, Dominica Willmann, Kerstin Petroll, Nadia Messaddeq, Laura Arrigoni, Thomas Manke, Jan-Wilhelm Kornfeld, Jens C Brüning, Vyacheslav Zagoriy, Michael Meret, Jörn Dengjel, Toufike Kanouni, Roland Schüle
Previous work indicated that lysine-specific demethylase 1 (Lsd1) can positively regulate the oxidative and thermogenic capacities of white and beige adipocytes. Here we investigate the role of Lsd1 in brown adipose tissue (BAT) and find that BAT-selective Lsd1 ablation induces a shift from oxidative to glycolytic metabolism. This shift is associated with downregulation of BAT-specific and upregulation of white adipose tissue (WAT)-selective gene expression. This results in the accumulation of di- and triacylglycerides and culminates in a profound whitening of BAT in aged Lsd1-deficient mice...
October 18, 2016: Cell Reports
Peng Zou, Longhua Liu, Louise D Zheng, Kyle K Payne, Masoud H Manjili, Michael O Idowu, Jinfeng Zhang, Eva M Schmelz, Zhiyong Cheng
Overactive mitochondrial fission was shown to promote cell transformation and tumor growth. It remains elusive how mitochondrial quality is regulated in such conditions. Here, we show that upregulation of mitochondrial fission protein, dynamin related protein-1 (Drp1), was accompanied with increased mitochondrial biogenesis markers (PGC1α, NRF1, and Tfam) in breast cancer cells. However, mitochondrial number was reduced, which was associated with lower mitochondrial oxidative capacity in breast cancer cells...
2016: Oxidative Medicine and Cellular Longevity
Amy E Mendham, Rob Duffield, Aaron J Coutts, Frank E Marino, Andriy Boyko, Andrew J McAinch, David John Bishop
PURPOSE: This study assessed the mitochondrial related signaling responses to a single bout of non-contact, modified football (touch rugby), played as small-sided games (SSG), or cycling (CYC) exercise in sedentary, obese, middle-aged men. METHOD: In a randomized, cross-over design, nine middle-aged, sedentary, obese men completed two, 40-min exercise conditions (CYC and SSG) separated by a 21-d recovery period. Heart rate (HR) and Ratings of Perceived Exertion were collected during each bout...
October 14, 2016: Journal of Applied Physiology
Shantaé M Thornton, James E Krolopp, Marcia J Abbott
Molecular mediators of metabolic processes, to increase energy expenditure, have become a focus for therapies of obesity. The discovery of cytokines secreted from the skeletal muscle (SKM), termed "myokines," has garnered attention due to their positive effects on metabolic processes. Interleukin-15 (IL-15) is a myokine that has numerous positive metabolic effects and is linked to the PPAR family of mitochondrial regulators. Here, we aimed to determine the importance of PPARα and/or PPARδ as targets of IL-15 signaling...
2016: PPAR Research
Fumiki Katsuoka, Hiromi Yamazaki, Masayuki Yamamoto
Nrf1 and Nrf2 (NF-E2-related factors 1 and 2, respectively) are transcription factors that belong to the Cap'n'collar (CNC) family and play critical roles in various tissues, including the liver. Liver-specific Nrf1 knockout mice show hepatic steatosis, accompanied by dysregulation of various metabolic genes. Nrf2 knockout mice show impairment in the induction of antioxidant and xenobiotic-metabolizing enzyme genes. Although it has been shown that small Maf (sMaf) proteins act as obligatory partners of CNC proteins, their precise contributions to the function of CNC proteins remain unclear especially in the context of adult liver functions...
October 10, 2016: Genes to Cells: Devoted to Molecular & Cellular Mechanisms
Larissa M Williams, Briony A Lago, Andrew G McArthur, Amogelang R Raphenya, Nicholas Pray, Nabil Saleem, Sophia Salas, Katherine Paulson, Roshni S Mangar, Yang Liu, Andy H Vo, Jordan A Shavit
Development is a complex and well-defined process characterized by rapid cell proliferation and apoptosis. At this stage in life, a developmentally young organism is more sensitive to toxicants as compared to an adult. In response to pro-oxidant exposure, members of the Cap'n'Collar (CNC) basic leucine zipper (b-ZIP) transcription factor family (including Nfe2 and Nfe2-related factors, Nrfs) activate the expression of genes whose protein products contribute to reduced toxicity. Here, we studied the role of the CNC protein, Nfe2, in the developmental response to pro-oxidant exposure in the zebrafish (Danio rerio)...
October 1, 2016: Aquatic Toxicology
Maria Manczak, Ramesh Kandimalla, David Fry, Hiromi Sesaki, P Hemachandra Reddy
The purpose of our study was to understand the protective effects of reduced expression of dynamin-related protein (Drp1) against amyloid beta (Aβ) induced mitochondrial and synaptic toxicities in Alzheimer's disease (AD) progression and pathogenesis. Our recent molecular and biochemical studies revealed that impaired mitochondrial dynamics - increased mitochondrial fragmentation and decreased fusion - in neurons from autopsy brains of AD patients and from transgenic AD mice and neurons expressing Aβ, suggesting that Aβ causes mitochondrial fragmentation in AD...
September 27, 2016: Human Molecular Genetics
Ramesh Kandimalla, Maria Manczak, David Fry, Yeguvapalli Suneetha, Hiromi Sesaki, P Hemachandra Reddy
The purpose of our study was to understand the protective effects of a partial reduction of dynamin-related protein 1 (Drp1) in Alzheimer's disease (AD) progression and pathogenesis. Increasing evidence suggests that phosphorylated Tau and mitochondrial abnormalities are involved in the loss of synapses, defective axonal transport and cognitive decline, in patients with AD. In the current study, we investigated whether a partial reduction of Drp1 protect neurons from phosphorylated Tau-induced mitochondrial and synaptic toxicities in AD progression...
September 15, 2016: Human Molecular Genetics
Kathleen M Mulvaney, Jacob P Matson, Priscila F Siesser, Tigist Y Tamir, Dennis Goldfarb, Timothy M Jacobs, Erica W Cloer, Joseph S Harrsion, Cyrus Vaziri, Jeanette G Cook, Michael B Major
KEAP1 is a substrate adaptor protein for a CUL3-based E3 ubiquitin ligase. Ubiquitylation and degradation of the antioxidant transcription factor NRF2 is considered the primary function of KEAP1; however, few other KEAP1 substrates have been identified. Because KEAP1 is altered in a number of human pathologies and has been proposed as a potential therapeutic target therein, we sought to better understand KEAP1 through systematic identification of its substrates. Towards this goal, we combined parallel affinity capture proteomics and candidate-based approaches...
September 12, 2016: Journal of Biological Chemistry
Tiande Zou, Bing Yu, Jie Yu, Xiangbing Mao, Ping Zheng, Jun He, Zhiqing Huang, Yue Liu, Daiwen Chen
BACKGROUND: Mitochondria are of major importance in oocyte and early embryo, playing a key role in maintaining energy homeostasis. Epidemiological findings indicate that maternal undernutrition-induced mitochondrial dysfunction during pregnancy is associated with the development of metabolic disorders in offspring. Here, we investigated the effects of moderately decreased maternal energy intake during pregnancy on skeletal muscle mitochondrial biogenesis in fetal offspring with pig as a model...
2016: Genes & Nutrition
Shun Koizumi, Taro Irie, Shoshiro Hirayama, Yasuyuki Sakurai, Hideki Yashiroda, Isao Naguro, Hidenori Ichijo, Jun Hamazaki, Shigeo Murata
In response to proteasome dysfunction, mammalian cells upregulate proteasome gene expression by activating Nrf1. Nrf1 is an endoplasmic reticulum-resident transcription factor that is continually retrotranslocated and degraded by the proteasome. Upon proteasome inhibition, Nrf1 escapes degradation and is cleaved to become active. However, the processing enzyme for Nrf1 remains obscure. Here we show that the aspartyl protease DNA-damage inducible 1 homolog 2 (DDI2) is required to cleave and activate Nrf1. Deletion of DDI2 reduced the cleaved form of Nrf1 and increased the full-length cytosolic form of Nrf1, resulting in poor upregulation of proteasomes in response to proteasome inhibition...
2016: ELife
Nicolas J Lehrbach, Gary Ruvkun
Proteasomes are essential for protein homeostasis in eukaryotes. To preserve cellular function, transcription of proteasome subunit genes is induced in response to proteasome dysfunction caused by pathogen attacks or proteasome inhibitor drugs. In Caenorhabditis elegans, this response requires SKN-1, a transcription factor related to mammalian Nrf1/2. Here, we use comprehensive genetic analyses to identify the pathway required for C. elegans to detect proteasome dysfunction and activate SKN-1. Genes required for SKN-1 activation encode regulators of ER traffic, a peptide N-glycanase, and DDI-1, a conserved aspartic protease...
2016: ELife
Fang-Hui Li, Hai-Tao Yu, Lin Xiao, Yan-Ying Liu
The aim of this study was to analyze the effects of exercise training on Bax and Bcl-2 protein content and sirtuin1 (SIRT1) mRNA expression levels to prevent sarcopenia in aging rats. Eight 18 months old male Sprague-Dawley rats were trained 5 days weekly for 8 weeks on a treadmill, and eight sedentary rats served as controls. Gastrocnemius muscles were dissected 2 days after the last training session. The mRNA content of PGC-1α, caspase-3, NRF1, TFAM, SOD2, and SIRT1 was estimated by RT-PCR with GAPDH used as an internal control...
2016: Advances in Experimental Medicine and Biology
Robert T Maughan, Eoin R Feeney, Emilie Capel, Jacqueline Capeau, Pere Domingo, Marta Giralt, Joep M A Lange, Praphan Phanuphak, David A Cooper, Peter Reiss, Patrick W G Mallon
OBJECTIVES: Use of ART containing HIV PIs has previously been associated with toxicity in subcutaneous adipose tissue (SAT), potentially contributing to the development of lipodystrophy and insulin resistance. However, the effect of PIs on SAT function in ART-naive patients independent of other ART classes is unknown. This study aimed to elucidate the effect of initiating PI-only ART on SAT function in ART-naive subjects. METHODS: In the HIVNAT-019 study, 48 HIV-infected, ART-naive Thai adults commencing PI-only ART comprising lopinavir/ritonavir/saquinavir for 24 weeks underwent assessments of fasting metabolic parameters and body composition...
August 11, 2016: Journal of Antimicrobial Chemotherapy
Artem P Gureev, Mikhail Yu Syromyatnikov, Tatyana M Gorbacheva, Anatoly A Starkov, Vasily N Popov
Age-related brain dysfunctions are frequently associated with deregulation of mitochondria functions and increased risk of developing neurodegenerative diseases (ND). Recently, a mitochondria-targeting drug methylene blue has been drawing considerable interest as a potential treatment for ND. We have compared the effect of MB treatment on the behavior, brain mitochondria reactive oxygen species generation, and gene expression in adult and aged mice. Aged mice manifested a decrease in physical endurance, spontaneous locomotor activity, and exploration concomitant with an increase in anxiety-related behavior, as compared to adult mice...
August 8, 2016: Neuroscience Research
Ram Babu Undi, Usha Gutti, Ravi Kumar Gutti
BACKGROUND: Megakaryocytes (MKs), a rare population of bone marrow cells, are responsible for the production of platelets. Sick neonates are predisposed to developing thrombocytopenia (platelet count <150×109/L) and neonates are affected by several megakaryocyte disorders as compared to adults. HYPOTHESIS: MicroRNAs (miRNAs) have been shown to crucially involve in the regulation of stem-cell differentiation in normal as well as malignant hematopoiesis, but their role in regulation of biological differences between adult and neonatal megakaryopoiesis is unknown...
October 2016: International Journal of Biochemistry & Cell Biology
Haitham E El-Sikhry, Nasser Alsaleh, Rambabu Dakarapu, John R Falck, John M Seubert
Maintenance of a healthy pool of mitochondria is important for the function and survival of terminally differentiated cells such as cardiomyocytes. Epoxyeicosatrienoic acids (EETs) are epoxy lipids derived from metabolism of arachidonic acid by cytochrome P450 epoxygenases. We have previously shown that EETs trigger a protective response limiting mitochondrial dysfunction and reducing cellular death. The aim of this study was to investigate whether EET-mediated effects influence mitochondrial quality in HL-1 cardiac cells during starvation...
2016: PloS One
Byung Geun Ha, Deok-Soo Moon, Hyeon Ju Kim, Yun Hee Shon
Recent studies showed that deficiencies of essential minerals including Mg, Ca, and K, and trace minerals including Se, Zn, and V, have implications for the development, prevention, and treatment of several chronic diseases including obesity and type 2 diabetes. Our previous studies revealed that balanced deep-sea water (BDSW), which is composed of desalinated water enriched with Mg and Ca, has potential as a treatment for diabetes and obesity. In this study, to determine whether BDSW regulates mitochondrial biogenesis and function, we investigated its effects on mitochondrial DNA (mtDNA) content, mitochondrial enzyme activity, expression of key transcription factors and mitochondria-specific genes, phosphorylation of signaling molecules associated with mitochondrial biogenesis, and mitochondrial function in 3T3-L1 preadipocytes...
July 16, 2016: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Kousuke Fukagai, Tsuyoshi Waku, A M Masudul Azad Chowdhury, Kaori Kubo, Mariko Matsumoto, Hiroki Kato, Tohru Natsume, Fuminori Tsuruta, Tomoki Chiba, Hiroaki Taniguchi, Akira Kobayashi
The transcriptional factor Nrf1 (NF-E2-related factor 1) sustains protein homeostasis (proteostasis) by regulating the expression of proteasome genes. Under physiological conditions, the transcriptional activity of Nrf1 is repressed by its sequestration into the endoplasmic reticulum (ER) and furthermore by two independent ubiquitin-proteasome pathways, comprising Hrd1 and β-TrCP in the cytoplasm and nucleus, respectively. However, the molecular mechanisms underlying Nrf1 activation remain unclear. Here, we report that USP15 (Ubiquitin-Specific Protease 15) activates Nrf1 in the nucleus by stabilizing it through deubiquitination...
September 9, 2016: Biochemical and Biophysical Research Communications
Yi Sun, Di Cui, Zhe Zhang, Qiang Zhang, Liu Ji, Shuzhe Ding
The discovery of miRNAs has brought the focus of physiologists to post-transcriptional regulation of the skeletal muscle. However, the field of how miRNAs are involved in regulating mitochondrial biogenesis and apoptosis of the skeletal muscle following endurance training is still in its infancy. Twelve male C57BL/6 mice were randomly assigned to either control group (Group C) or voluntary wheel running group (Group E). The Group C was housed in cages mounted with fixed wheels, while mice of Group E were allowed to run on wheels freely for eight weeks...
July 9, 2016: Comparative Biochemistry and Physiology. Part B, Biochemistry & Molecular Biology
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