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BCAA & mitochondrial dysfunction

Davis S Sonnet, Monique N O'Leary, Mark A Gutierrez, Steven M Nguyen, Samiha Mateen, Yuehmei Hsu, Kylie P Mitchell, Antonio J Lopez, Jerry Vockley, Brian K Kennedy, Arvind Ramanathan
Maple Syrup Urine Disease (MSUD) is an inherited disorder caused by the dysfunction in the branched chain keto-acid dehydrogenase (BCKDH) enzyme. This leads to buildup of branched-chain keto-acids (BCKA) and branched-chain amino acids (BCAA) in body fluids (e.g. keto-isocaproic acid from the BCAA leucine), leading to numerous clinical features including a less understood skeletal muscle dysfunction in patients. KIC is an inhibitor of mitochondrial function at disease relevant concentrations. A murine model of intermediate MSUD (iMSUD) shows significant skeletal muscle dysfunction as by judged decreased muscle fiber diameter...
2016: Scientific Reports
Petri Wiklund, Xiaobo Zhang, Satu Pekkala, Reija Autio, Lingjia Kong, Yifan Yang, Sirkka Keinänen-Kiukaanniemi, Markku Alen, Sulin Cheng
Insulin resistance is associated adiposity, but the mechanisms are not fully understood. In this study, we aimed to identify early metabolic alterations associated with insulin resistance in normoglycemic women with varying degree of adiposity. One-hundred and ten young and middle-aged women were divided into low and high IR groups based on their median HOMA-IR (0.9 ± 0.4 vs. 2.8 ± 1.2). Body composition was assessed using DXA, skeletal muscle and liver fat by proton magnetic resonance spectroscopy, serum metabolites by nuclear magnetic resonance spectroscopy and adipose tissue and skeletal muscle gene expression by microarrays...
2016: Scientific Reports
A Oyarzabal, I Bravo-Alonso, M Sánchez-Aragó, M T Rejas, B Merinero, A García-Cazorla, R Artuch, M Ugarte, P Rodríguez-Pombo
Mutations on the mitochondrial-expressed Branched Chain α-Keto acid Dehydrogenase Kinase (BCKDK) gene have been recently associated with a novel dietary-treatable form of autism. But, being a mitochondrial metabolism disease, little is known about the impact on mitochondrial performance. Here, we analyze the mitochondrial response to the BCKDK-deficiency in patient's primary fibroblasts by measuring bioenergetics, ultra-structural and dynamic parameters. A two-fold increase in superoxide anion production, together with a reduction in ATP-linked respiration and intracellular ATP levels (down to 60%) detected in mutants fibroblasts point to a general bioenergetics depletion that could affect the mitochondrial dynamics and cell fate...
April 2016: Biochimica et Biophysica Acta
Sulin Cheng, Petri Wiklund, Reija Autio, Ronald Borra, Xiaowei Ojanen, Leiting Xu, Timo Törmäkangas, Markku Alen
BACKGROUND: Fatty liver is a major cause of obesity-related morbidity and mortality. The aim of this study was to identify early metabolic alterations associated with liver fat accumulation in 50- to 55-year-old men (n = 49) and women (n = 52) with and without NAFLD. METHODS: Hepatic fat content was measured using proton magnetic resonance spectroscopy (1H MRS). Serum samples were analyzed using a nuclear magnetic resonance (NMR) metabolomics platform. Global gene expression profiles of adipose tissues and skeletal muscle were analyzed using Affymetrix microarrays and quantitative PCR...
2015: PloS One
Nishanth E Sunny, Srilaxmi Kalavalapalli, Fernando Bril, Timothy J Garrett, Manisha Nautiyal, Justin T Mathew, Caroline M Williams, Kenneth Cusi
Elevated plasma branched-chain amino acids (BCAA) in the setting of insulin resistance have been relevant in predicting type 2 diabetes mellitus (T2DM) onset, but their role in the etiology of hepatic insulin resistance remains uncertain. We determined the link between BCAA and dysfunctional hepatic tricarboxylic acid (TCA) cycle, which is a central feature of hepatic insulin resistance and nonalcoholic fatty liver disease (NAFLD). Plasma metabolites under basal fasting and euglycemic hyperinsulinemic clamps (insulin stimulation) were measured in 94 human subjects with varying degrees of insulin sensitivity to identify their relationships with insulin resistance...
August 15, 2015: American Journal of Physiology. Endocrinology and Metabolism
Christopher J Lynch, Sean H Adams
Branched-chain amino acids (BCAAs) are important nutrient signals that have direct and indirect effects. Frequently, BCAAs have been reported to mediate antiobesity effects, especially in rodent models. However, circulating levels of BCAAs tend to be increased in individuals with obesity and are associated with worse metabolic health and future insulin resistance or type 2 diabetes mellitus (T2DM). A hypothesized mechanism linking increased levels of BCAAs and T2DM involves leucine-mediated activation of the mammalian target of rapamycin complex 1 (mTORC1), which results in uncoupling of insulin signalling at an early stage...
December 2014: Nature Reviews. Endocrinology
Janne M Strand, Ragnhild Skinnes, Katja Scheffler, Terje Rootvelt, Berit Woldseth, Magnar Bjørås, Lars Eide
OBJECTIVE: The mitochondrial branched-chain ketoacid dehydrogenase (BCKD) catalyzes the degradation of branched-chain amino acids (BCAA), which have been shown to induce oxidative stress. Maple Syrup Urine Disease (MSUD) is caused by impaired activity of BCKD, suggesting that oxidative stress and resulting DNA damage could contribute to pathology. We evaluated the potential effect of BCKD deficiency on genome integrity and mitochondrial function as a downstream target. METHODS: Primary fibroblasts from MSUD patients and controls were either cultivated under normal conditions or exposed to metabolic or oxidative stress...
August 2014: Metabolism: Clinical and Experimental
Kristine C Olson, Gang Chen, Yuping Xu, Andras Hajnal, Christopher J Lynch
OBJECTIVE: Circulating branched-chain amino acids (BCAAs) are elevated in obesity and this has been linked to obesity comorbidities. However it is unclear how obesity affects alloisoleucine, a BCAA and pathognomonic marker of branched-chain keto acid dehydrogenase complex (BCKDC) disorders. It has been previously established that obese Zucker rats exhibit BCKDC impairments in fat and other tissues, whereas BCKDC impairments in adipose tissue of DIO rats are compensated by increased hepatic BCKDC activity...
May 2014: Obesity
Colleen Clarke, Rui Xiao, Emily Place, Zhe Zhang, Neal Sondheimer, Michael Bennett, Marc Yudkoff, Marni J Falk
UNLABELLED: Diagnosing primary mitochondrial respiratory chain (RC) dysfunction has long relied on invasive tissue biopsies, since no blood-based biomarker has been shown to have sufficiently high sensitivity and specificity across the myriad of individual clinical presentations. We sought to determine whether cohort-level evaluation of commonly obtained blood analytes might reveal consistent patterns to discriminate a heterogenous group of primary mitochondrial RC disease subjects both from control individuals and from subjects with pyruvate dehydrogenase deficiency...
September 2013: Molecular Genetics and Metabolism
Tatjana M Hildebrandt, Ivano Di Meo, Massimo Zeviani, Carlo Viscomi, Hans-Peter Braun
Hydrogen sulfide is a physiologically relevant signalling molecule. However, circulating levels of this highly biologically active substance have to be maintained within tightly controlled limits in order to avoid toxic side effects. In patients suffering from EE (ethylmalonic encephalopathy), a block in sulfide oxidation at the level of the SDO (sulfur dioxygenase) ETHE1 leads to severe dysfunctions in microcirculation and cellular energy metabolism. We used an Ethe1-deficient mouse model to investigate the effect of increased sulfide and persulfide concentrations on liver, kidney, muscle and brain proteomes...
2013: Bioscience Reports
Giselli Scaini, Lis Mairá Mello-Santos, Camila B Furlanetto, Isabela C Jeremias, Francielle Mina, Patrícia F Schuck, Gustavo C Ferreira, Luiza W Kist, Talita C B Pereira, Maurício R Bogo, Emilio L Streck
Maple syrup urine disease (MSUD) is a neurometabolic disorder caused by deficiency of the activity of the mitochondrial enzyme complex branched-chain α-keto acid dehydrogenase leading to accumulation of the branched-chain amino acids (BCAA) and their corresponding branched-chain α-keto acids. In this study, we examined the effects of acute and chronic administration of BCAA on protein levels and mRNA expression of nerve growth factor (NGF) considering that patients with MSUD present neurological dysfunction and cognitive impairment...
December 2013: Molecular Neurobiology
Caroline Mescka, Tarsila Moraes, Andrea Rosa, Priscila Mazzola, Bruna Piccoli, Carlos Jacques, Giovana Dalazen, Juliana Coelho, Marcelo Cortes, Melaine Terra, Carmen Regla Vargas, Carlos S Dutra-Filho
Maple syrup urine disease (MSUD) is an autosomal recessive inborn error of metabolism caused by deficiency of the activity of the mitochondrial enzyme complex branched-chain α-keto acid dehydrogenase (BCKAD) leading to accumulation of the branched-chain amino acids (BCAA) leucine, isoleucine and valine and their corresponding branched-chain α-keto acids. Affected patients present severe brain dysfunction manifested such as ataxia, seizures, coma, psychomotor delay and mental retardation. The mechanisms of brain damage in this disease remain poorly understood...
March 2011: Metabolic Brain Disease
Natalie Lefort, Brian Glancy, Benjamin Bowen, Wayne T Willis, Zachary Bailowitz, Elena A De Filippis, Colleen Brophy, Christian Meyer, Kurt Højlund, Zhengping Yi, Lawrence J Mandarino
OBJECTIVE: The contribution of mitochondrial dysfunction to skeletal muscle insulin resistance remains elusive. Comparative proteomics are being applied to generate new hypotheses in human biology and were applied here to isolated mitochondria to identify novel changes in mitochondrial protein abundance present in insulin-resistant muscle. RESEARCH DESIGN AND METHODS: Mitochondria were isolated from vastus lateralis muscle from lean and insulin-sensitive individuals and from obese and insulin-resistant individuals who were otherwise healthy...
October 2010: Diabetes
Susan C Connor, Michael K Hansen, Adam Corner, Randall F Smith, Terence E Ryan
Type 2 diabetes (T2D), one of the most common diseases in the western world, is characterized by insulin resistance and impaired beta-cell function but currently it is difficult to determine the precise pathophysiology in individual T2D patients. Non-targeted metabolomics technologies have the potential for providing novel biomarkers of disease and drug efficacy, and are increasingly being incorporated into biomarker exploration studies. Contextualization of metabolomics results is enhanced by integration of study data from other platforms, such as transcriptomics, thus linking known metabolites and genes to relevant biochemical pathways...
May 2010: Molecular BioSystems
Susan M Hutson, Andrew J Sweatt, Kathryn F Lanoue
There are several features of the metabolism of the indispensable BCAAs that set them apart from other indispensable amino acids. BCAA catabolism involves 2 initial enzymatic steps that are common to all 3 BCAAs; therefore, the dietary intake of an individual BCAA impacts on the catabolism of all 3. The first step is reversible transamination followed by irreversible oxidative decarboxylation of the branched-chain alpha-keto acid transamination products, the branched chain alpha-keto acids (BCKAs). The BCAA catabolic enzymes are distributed widely in body tissues and, with the exception of the nervous system, all reactions occur in the mitochondria of the cell...
June 2005: Journal of Nutrition
Robert A Harris, Mandar Joshi, Nam Ho Jeoung, Mariko Obayashi
The branched-chain amino acids (BCAAs) are required for protein synthesis and neurotransmitter synthesis. The branched-chain alpha-ketoacid dehydrogenase complex (BCKDC) is the most important regulatory enzyme in the catabolic pathways of the BCAAs. Activity of the complex is controlled by covalent modification with phosphorylation of its branched-chain alpha-ketoacid dehydrogenase subunits by a specific kinase [branched-chain kinase (BDK)] causing inactivation and dephosphorylation by a specific phosphatase [branched-chain phosphatase (BDP)] causing activation...
June 2005: Journal of Nutrition
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