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OXPHOS disorder

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https://www.readbyqxmd.com/read/28716914/metabolic-profiles-of-exercise-in-patients-with-mcardle-disease-or-mitochondrial-myopathy
#1
Nigel F Delaney, Rohit Sharma, Laura Tadvalkar, Clary B Clish, Ronald G Haller, Vamsi K Mootha
McArdle disease and mitochondrial myopathy impair muscle oxidative phosphorylation (OXPHOS) by distinct mechanisms: the former by restricting oxidative substrate availability caused by blocked glycogen breakdown, the latter because of intrinsic respiratory chain defects. We applied metabolic profiling to systematically interrogate these disorders at rest, when muscle symptoms are typically minimal, and with exercise, when symptoms of premature fatigue and potential muscle injury are unmasked. At rest, patients with mitochondrial disease exhibit elevated lactate and reduced uridine; in McArdle disease purine nucleotide metabolites, including xanthine, hypoxanthine, and inosine are elevated...
July 17, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28686290/mining-for-mitochondrial-mechanisms-linking-known-syndromes-to-mitochondrial-function
#2
REVIEW
Daan M Panneman, Jan A Smeitink, Richard J Rodenburg
Mitochondrial disorders (MDs) are caused by defects in one or multiple complexes of the oxidative phosphorylation (OXPHOS) machinery. MDs are associated with a broad range of clinical signs and symptoms, and have considerable clinical overlap with other neuromuscular syndromes. This overlap might be due to involvement of mitochondrial pathways in some of these non-mitochondrial syndromes. Here, we give an overview of around 25 non-mitochondrial syndromes, diagnosed in patients who were initially suspected to have a MD on the basis of clinical and biochemical parameters...
July 7, 2017: Clinical Genetics
https://www.readbyqxmd.com/read/28646906/modulation-of-oxidative-phosphorylation-and-redox-homeostasis-in-mitochondrial-ndufs4-deficiency-via-mesenchymal-stem-cells
#3
Marlen Melcher, Katharina Danhauser, Annette Seibt, Özer Degistirici, Fabian Baertling, Arun Kumar Kondadi, Andreas S Reichert, Werner J H Koopman, Peter H G M Willems, Richard J Rodenburg, Ertan Mayatepek, Roland Meisel, Felix Distelmaier
BACKGROUND: Disorders of the oxidative phosphorylation (OXPHOS) system represent a large group among the inborn errors of metabolism. The most frequently observed biochemical defect is isolated deficiency of mitochondrial complex I (CI). No effective treatment strategies for CI deficiency are so far available. The purpose of this study was to investigate whether and how mesenchymal stem cells (MSCs) are able to modulate metabolic function in fibroblast cell models of CI deficiency. METHODS: We used human and murine fibroblasts with a defect in the nuclear DNA encoded NDUFS4 subunit of CI...
June 24, 2017: Stem Cell Research & Therapy
https://www.readbyqxmd.com/read/28575497/loss-of-hepatic-lrpprc-alters-mitochondrial-bioenergetics-regulation-of-permeability-transition-and-trans-membrane-ros-diffusion
#4
Alexanne Cuillerier, Shamisa Honarmand, Virgilio J J Cadete, Matthieu Ruiz, Anik Forest, Sonia Deschênes, Claudine Beauchamp, Guy Charron, John D Rioux, Christine Des Rosiers, Eric A Shoubridge, Yan Burelle
BACKGROUND AND AIMS: The French-Canadian variant of Leigh Syndrome (LSFC) is an autosomal recessive oxidative phosphorylation (OXPHOS) disorder caused by a mutation in LRPPRC, coding for a protein involved in the stability of mitochondrially-encoded mRNAs. Low levels of LRPPRC are present in all patient tissues, but result in a disproportionately severe OXPHOS defect in the brain and liver, leading to unpredictable subacute metabolic crises. METHODS: To investigate the impact of the OXPHOS defect in the liver, we analyzed the mitochondrial phenotype in mice harboring an hepatocyte-specific inactivation of Lrpprc...
May 31, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28552678/detection-of-6-demethoxyubiquinone-in-coq10-deficiency-disorders-insights-into-enzyme-interactions-and-identification-of-potential-therapeutics
#5
Diran Herebian, Annette Seibt, Sander H J Smits, Gisela Bünning, Christoph Freyer, Holger Prokisch, Daniela Karall, Anna Wredenberg, Anna Wedell, Luis C López, Ertan Mayatepek, Felix Distelmaier
Coenzyme Q10 (CoQ10) is an essential cofactor of the mitochondrial oxidative phosphorylation (OXPHOS) system and its deficiency has important implications for several inherited metabolic disorders of childhood. The biosynthesis of CoQ10 is a complicated process, which involves at least 12 different enzymes. One of the metabolic intermediates that are formed during CoQ10 biosynthesis is the molecule 6-demethoxyubiquinone (6-DMQ). This CoQ precursor is processed at the level of COQ7 and COQ9. We selected this metabolite as a marker substance for metabolic analysis of cell lines with inherited genetic defects (COQ2, COQ4, COQ7 and COQ9) or siRNA knockdown in CoQ biosynthesis enzymes using ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS)...
May 20, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28438601/who-and-how-in-the-regulation-of-mitochondrial-cristae-shape-and-function
#6
R Quintana-Cabrera, A Mehrotra, G Rigoni, M E Soriano
Mitochondrial adaptation to different physiological conditions highly relies on the regulation of mitochondrial ultrastructure, particularly at the level of cristae compartment. Cristae represent the membrane hub where most of the respiratory complexes embed to account for OXPHOS and energy production in the form of adenosine triphosphate (ATP). Changes in cristae number and shape define the respiratory capacity as well as cell viability. The identification of key regulators of cristae morphology and the understanding of their contribution to the mitochondrial ultrastructure and function have become an strategic goal to understand mitochondrial disorders and to exploit as therapeutic targets...
April 21, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28380427/glucose-availability-controls-atf4-mediated-mitf-suppression-to-drive-melanoma-cell-growth
#7
Jennifer Ferguson, Michael Smith, Isabel Zudaire, Claudia Wellbrock, Imanol Arozarena
It is well know that cancer cells have adopted an altered metabolism and that glucose is a major source of energy for these cells. In melanoma, enhanced glucose usage is favoured through the hyper-activated MAPK pathway, which suppresses OXPHOS and stimulates glycolysis. However, it has not been addressed how glucose availability impacts on melanoma specific signaling pathways that drive melanoma cell proliferation. Here we show that melanoma cells are dependent on high glucose levels for efficient growth. Thereby, glucose metabolism controls the expression of the melanoma fate transcription factor MITF, a master regulator of melanoma cell survival and proliferation, invasion and therapy resistance...
May 16, 2017: Oncotarget
https://www.readbyqxmd.com/read/28357370/attenuation-of-polyglutamine-induced-toxicity-by-enhancement-of-mitochondrial-oxphos-in-yeast-and-fly-models-of-aging
#8
Andrea L Ruetenik, Alejandro Ocampo, Kai Ruan, Yi Zhu, Chong Li, R Grace Zhai, Antoni Barrientos
Defects in mitochondrial biogenesis and function are common in many neurodegenerative disorders, including Huntington's disease (HD). We have previously shown that in yeast models of HD, enhancement of mitochondrial biogenesis through overexpression of Hap4, the catalytic subunit of the transcriptional complex that regulates mitochondrial gene expression, alleviates the growth arrest induced by expanded polyglutamine (polyQ) tract peptides in rapidly dividing cells. However, the mechanism through which HAP4 overexpression exerts this protection remains unclear...
July 26, 2016: Microbial Cell
https://www.readbyqxmd.com/read/28351484/hypocapnic-hypothesis-of-leigh-disease
#9
Ewa Pronicka
Leigh syndrome (LS) is a neurogenetic disorder of children caused by mutations in at least 75 genes which impair mitochondrial bioenergetics. The changes have typical localization in basal ganglia and brainstem, and typical histological picture of spongiform appearance, vascular proliferation and gliosis. ATP deprivation, free radicals and lactate accumulation are suspected to be the causes. Hypocapnic hypothesis proposed in the paper questions the energy deprivation as the mechanism of LS. We assume that the primary harmful factor is hypocapnia (decrease in pCO2) and respiratory alkalosis (increase in pH) due to hyperventilation, permanent or in response to stress...
April 2017: Medical Hypotheses
https://www.readbyqxmd.com/read/28285835/regulation-of-mammalian-mitochondrial-gene-expression-recent-advances
#10
REVIEW
Sarah F Pearce, Pedro Rebelo-Guiomar, Aaron R D'Souza, Christopher A Powell, Lindsey Van Haute, Michal Minczuk
Perturbation of mitochondrial DNA (mtDNA) gene expression can lead to human pathologies. Therefore, a greater appreciation of the basic mechanisms of mitochondrial gene expression is desirable to understand the pathophysiology of associated disorders. Although the purpose of the mitochondrial gene expression machinery is to provide only 13 proteins of the oxidative phosphorylation (OxPhos) system, recent studies have revealed its remarkable and unexpected complexity. We review here the latest breakthroughs in our understanding of the post-transcriptional processes of mitochondrial gene expression, focusing on advances in analyzing the mitochondrial epitranscriptome, the role of mitochondrial RNA granules (MRGs), the benefits of recently obtained structures of the mitochondrial ribosome, and the coordination of mitochondrial and cytosolic translation to orchestrate the biogenesis of OxPhos complexes...
March 9, 2017: Trends in Biochemical Sciences
https://www.readbyqxmd.com/read/28216230/activation-of-a-cryptic-splice-site-in-the-mitochondrial-elongation-factor-gfm1-causes-combined-oxphos-deficiency
#11
Mariella T Simon, Bobby G Ng, Marisa W Friederich, Raymond Y Wang, Monica Boyer, Martin Kircher, Renata Collard, Kati J Buckingham, Richard Chang, Jay Shendure, Deborah A Nickerson, Michael J Bamshad, Johan L K Van Hove, Hudson H Freeze, Jose E Abdenur
We report the clinical, biochemical, and molecular findings in two brothers with encephalopathy and multi-systemic disease. Abnormal transferrin glycoforms were suggestive of a type I congenital disorder of glycosylation (CDG). While exome sequencing was negative for CDG related candidate genes, the testing revealed compound heterozygous mutations in the mitochondrial elongation factor G gene (GFM1). One of the mutations had been reported previously while the second, novel variant was found deep in intron 6, activating a cryptic splice site...
May 2017: Mitochondrion
https://www.readbyqxmd.com/read/28025489/the-effects-of-ascorbate-n-acetylcysteine-and-resveratrol-on-fibroblasts-from-patients-with-mitochondrial-disorders
#12
Liza Douiev, Devorah Soiferman, Corinne Alban, Ann Saada
Reactive oxygen species (ROS) are assumed to be implicated in the pathogenesis of inborn mitochondrial diseases affecting oxidative phosphorylation (OXPHOS). In the current study, we characterized the effects of three small molecules with antioxidant properties (N-acetylcysteine, ascorbate, and resveratrol) on ROS production and several OXPHOS parameters (growth in glucose free medium, ATP production, mitochondrial content and membrane potential (MMP)), in primary fibroblasts derived from seven patients with different molecularly defined and undefined mitochondrial diseases...
December 22, 2016: Journal of Clinical Medicine
https://www.readbyqxmd.com/read/27974213/reversal-of-defective-mitochondrial-biogenesis-in-limb-girdle-muscular-dystrophy-2d-by-independent-modulation-of-histone-and-pgc-1%C3%AE-acetylation
#13
Sarah Pambianco, Matteo Giovarelli, Cristiana Perrotta, Silvia Zecchini, Davide Cervia, Ilaria Di Renzo, Claudia Moscheni, Michela Ripolone, Raffaella Violano, Maurizio Moggio, Maria Teresa Bassi, Pier Lorenzo Puri, Lucia Latella, Emilio Clementi, Clara De Palma
Mitochondrial dysfunction occurs in many muscle degenerative disorders. Here, we demonstrate that mitochondrial biogenesis was impaired in limb-girdle muscular dystrophy (LGMD) 2D patients and mice and was associated with impaired OxPhos capacity. Two distinct approaches that modulated histones or peroxisome proliferator-activated receptor-gamma coactivator 1 α (PGC-1α) acetylation exerted equivalent functional effects by targeting different mitochondrial pathways (mitochondrial biogenesis or fatty acid oxidation[FAO])...
December 13, 2016: Cell Reports
https://www.readbyqxmd.com/read/27826120/mitochondrial-oxidative-phosphorylation-disorders-in-children-phenotypic-genotypic-and-biochemical-correlations-in-85-patients-from-south-india
#14
Kothari Sonam, Parayil Sankaran Bindu, M M Srinivas Bharath, Periyasamy Govindaraj, Narayanappa Gayathri, Hanumanthapura R Arvinda, Shwetha Chiplunkar, Madhu Nagappa, Sanjib Sinha, Nahid Akhtar Khan, Vandana Nunia, Arumugam Paramasivam, Kumarasamy Thangaraj, Arun B Taly
Mitochondrial oxidative phosphorylation (OXPHOS) disorders account for a variety of neuromuscular disorders in children. In this study mitochondrial respiratory chain enzymes were assayed in muscle tissue in a large cohort of children with varied neuromuscular presentations from June 2011 to December 2013. The biochemical enzyme deficiencies were correlated with the phenotypes, magnetic resonance imaging, histopathology and genetic findings to reach a final diagnosis. There were 85 children (mean age: 6.9±4...
January 2017: Mitochondrion
https://www.readbyqxmd.com/read/27812541/muscle-oxidative-phosphorylation-quantitation-using-creatine-chemical-exchange-saturation-transfer-crcest-mri-in-mitochondrial-disorders
#15
Catherine DeBrosse, Ravi Prakash Reddy Nanga, Neil Wilson, Kevin D'Aquilla, Mark Elliott, Hari Hariharan, Felicia Yan, Kristin Wade, Sara Nguyen, Diana Worsley, Chevonne Parris-Skeete, Elizabeth McCormick, Rui Xiao, Zuela Zolkipli Cunningham, Lauren Fishbein, Katherine L Nathanson, David R Lynch, Virginia A Stallings, Marc Yudkoff, Marni J Falk, Ravinder Reddy, Shana E McCormack
Systemic mitochondrial energy deficiency is implicated in the pathophysiology of many age-related human diseases. Currently available tools to estimate mitochondrial oxidative phosphorylation (OXPHOS) capacity in skeletal muscle in vivo lack high anatomic resolution. Muscle groups vary with respect to their contractile and metabolic properties. Therefore, muscle group-specific estimates of OXPHOS would be advantageous. To address this need, a noninvasive creatine chemical exchange saturation transfer (CrCEST) MRI technique has recently been developed, which provides a measure of free creatine...
November 3, 2016: JCI Insight
https://www.readbyqxmd.com/read/27713486/the-phasor-flim-fingerprints-reveal-shifts-from-oxphos-to-enhanced-glycolysis-in-huntington-disease
#16
Sara Sameni, Adeela Syed, J Lawrence Marsh, Michelle A Digman
Huntington disease (HD) is an autosomal neurodegenerative disorder caused by the expansion of Polyglutamine (polyQ) in exon 1 of the Huntingtin protein. Glutamine repeats below 36 are considered normal while repeats above 40 lead to HD. Impairment in energy metabolism is a common trend in Huntington pathogenesis; however, this effect is not fully understood. Here, we used the phasor approach and Fluorescence Lifetime Imaging Microscopy (FLIM) to measure changes between free and bound fractions of NADH as a indirect measure of metabolic alteration in living cells...
October 7, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27696117/pathogenic-variants-in-htra2-cause-an-early-onset-mitochondrial-syndrome-associated-with-3-methylglutaconic-aciduria
#17
Monika Oláhová, Kyle Thompson, Steven A Hardy, Inês A Barbosa, Arnaud Besse, Maria-Eleni Anagnostou, Kathryn White, Tracey Davey, Michael A Simpson, Michael Champion, Greg Enns, Susan Schelley, Robert N Lightowlers, Zofia M A Chrzanowska-Lightowlers, Robert McFarland, Charu Deshpande, Penelope E Bonnen, Robert W Taylor
Mitochondrial diseases collectively represent one of the most heterogeneous group of metabolic disorders. Symptoms can manifest at any age, presenting with isolated or multiple-organ involvement. Advances in next-generation sequencing strategies have greatly enhanced the diagnosis of patients with mitochondrial disease, particularly where a mitochondrial aetiology is strongly suspected yet OXPHOS activities in biopsied tissue samples appear normal. We used whole exome sequencing (WES) to identify the molecular basis of an early-onset mitochondrial syndrome-pathogenic biallelic variants in the HTRA2 gene, encoding a mitochondria-localised serine protease-in five subjects from two unrelated families characterised by seizures, neutropenia, hypotonia and cardio-respiratory problems...
January 2017: Journal of Inherited Metabolic Disease
https://www.readbyqxmd.com/read/27666594/bromodomain-inhibitors-correct-bioenergetic-deficiency-caused-by-mitochondrial-disease-complex-i-mutations
#18
Joeva J Barrow, Eduardo Balsa, Francisco Verdeguer, Clint D J Tavares, Meghan S Soustek, Louis R Hollingsworth, Mark Jedrychowski, Rutger Vogel, Joao A Paulo, Jan Smeitink, Steve P Gygi, John Doench, David E Root, Pere Puigserver
Mitochondrial diseases comprise a heterogeneous group of genetically inherited disorders that cause failures in energetic and metabolic function. Boosting residual oxidative phosphorylation (OXPHOS) activity can partially correct these failures. Herein, using a high-throughput chemical screen, we identified the bromodomain inhibitor I-BET 525762A as one of the top hits that increases COX5a protein levels in complex I (CI) mutant cybrid cells. In parallel, bromodomain-containing protein 4 (BRD4), a target of I-BET 525762A, was identified using a genome-wide CRISPR screen to search for genes whose loss of function rescues death of CI-impaired cybrids grown under conditions requiring OXPHOS activity for survival...
October 6, 2016: Molecular Cell
https://www.readbyqxmd.com/read/27618766/myoclonus-epilepsy-in-mitochondrial-disorders
#19
REVIEW
Costanza Lamperti, Massimo Zeviani
Mitochondrial disorders is a group of clinical entities associated with abnormalities of the mitochondrial respiratory chain (MRC), which carries out the oxidative phosphorylation (OXPHOS) of ADP into ATP. As the MRC is the result of genetic complementation between two separate genomes, nuclear and mitochondrial, OXPHOS failure can derive from mutations in either nuclear-encoded, or mitochondrial-encoded, genes. Epilepsy is a relatively common feature of mitochondrial disease, especially in early-onset encephalopathies of infants and children...
September 1, 2016: Epileptic Disorders: International Epilepsy Journal with Videotape
https://www.readbyqxmd.com/read/27597947/dynamics-of-human-mitochondrial-complex-i-assembly-implications-for-neurodegenerative-diseases
#20
REVIEW
Gabriele Giachin, Romain Bouverot, Samira Acajjaoui, Serena Pantalone, Montserrat Soler-López
Neurons are extremely energy demanding cells and highly dependent on the mitochondrial oxidative phosphorylation (OXPHOS) system. Mitochondria generate the energetic potential via the respiratory complexes I to IV, which constitute the electron transport chain (ETC), together with complex V. These redox reactions release energy in the form of ATP and also generate reactive oxygen species (ROS) that are involved in cell signaling but can eventually lead to oxidative stress. Complex I (CI or NADH:ubiquinone oxidoreductase) is the largest ETC enzyme, containing 44 subunits and the main contributor to ROS production...
2016: Frontiers in Molecular Biosciences
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