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Philip A. Wood - One of the best experts on this subject based on the ideXlab platform.

  • synergistic heterozygosity in mice with inherited Enzyme Deficiencies of mitochondrial fatty acid β oxidation
    Molecular Genetics and Metabolism, 2005
    Co-Authors: Michele A Schuler, Jerry Vockley, Piero Rinaldo, Philip A. Wood, Barbara A Gower, Dietrich Matern
    Abstract:

    Abstract We have used mice with inborn errors of mitochondrial fatty acid β-oxidation to test the concept of synergistic heterozygosity. We postulated that clinical disease can result from heterozygous mutations in more than one gene in single or related metabolic pathways. Mice with combinations of mutations in mitochondrial fatty acid β-oxidation genes were cold challenged to test their ability to maintain normal body temperature, a sensitive indicator of overall β-oxidation function. This included mice of the following genotypes: triple heterozygosity for mutations in very-long-chain acyl CoA dehydrogenase, long-chain acyl CoA dehydrogenase, and short-chain acyl CoA dehydrogenase genes (VLCAD+/−//LCAD+/−//SCAD+/−); double heterozygosity for mutations in VLCAD and LCAD genes (VLCAD+/−//LCAD+/−); double heterozygosity for mutations in LCAD and SCAD genes (LCAD+/−//SCAD+/−); single heterozygous mice (VLCAD+/−, LCAD+/−, SCAD+/−) and wild-type. We found that approximately 33% of mice with any of the combined mutant genotypes tested became hypothermic during a cold challenge. All wild-type and single heterozygous mice maintained normal body temperature throughout a cold challenge. Despite development of hypothermia in some double heterozygous mice, blood glucose concentrations remained normal. Biochemical screening by acylcarnitine and fatty acid analyses demonstrated results that varied by genotype. Thus, physiologic reduction of the β-oxidation pathway, characterized as cold intolerance, occurred in mice with double or triple heterozygosity; however, the derangement was milder than in mice homozygous for any of these mutations. These results substantiate the concept of synergistic heterozygosity and illustrate the potential complexity involved in diagnosis and characterization of inborn errors of fatty acid metabolism in humans.

  • Functional Correction of Short-Chain Acyl-CoA Dehydrogenase Deficiency in Transgenic Mice: Implications for Gene Therapy of Human Mitochondrial Enzyme Deficiencies
    Human molecular genetics, 1997
    Co-Authors: C.lisa Kelly, William J. Rhead, William Kutschke, Amy E. Brix, Doug A. Hamm, Carl A. Pinkert, J. Russell Lindsey, Philip A. Wood
    Abstract:

    We report the therapeutic effects of liver-specific expression of a short-chain acyl-CoA dehydrogenase (SCAD) transgene in the SCAD-deficient mouse model. Transgenic mice were produced with a rat albumin promoter/enhancer driving a mouse SCAD minigene (ALB-SCAD) on both the SCAD normal genetic background and a SCAD-deficient background. In three transgenic lines produced on the SCAD-deficient background, recombinant SCAD activity and antigen in liver mitochondria were found up to 7-fold of normal control values. All three lines showed a markedly reduced organic aciduria and fatty liver, which are sensitive indicators of the metabolic abnormality seen in this disease found in children. We found no detrimental effects of high liver SCAD expression in transgenic mice on either background. These studies provide important basic and practical therapeutic information for the potential gene therapy of nuclear-encoded mitochondrial Enzyme Deficiencies, as well as insights into the mechanisms of the disease.

Lara Abulhoul - One of the best experts on this subject based on the ideXlab platform.

Simon J R Heales - One of the best experts on this subject based on the ideXlab platform.

Rolf Wibom - One of the best experts on this subject based on the ideXlab platform.

  • clinical presentation genetic etiology and coEnzyme q10 levels in 55 children with combined Enzyme Deficiencies of the mitochondrial respiratory chain
    The Journal of Pediatrics, 2021
    Co-Authors: Karin Naess, Helene Bruhn, Henrik Stranneheim, Christoph Freyer, Rolf Wibom
    Abstract:

    Objectives To evaluate the clinical symptoms and biochemical findings and establish the genetic etiology in a cohort of pediatric patients with combined Deficiencies of the mitochondrial respiratory chain complexes. Study design Clinical and biochemical data were collected from 55 children. All patients were subjected to sequence analysis of the entire mitochondrial genome, except when the causative mutations had been identified based on the clinical picture. Whole exome sequencing/whole genome sequencing (WES/WGS) was performed in 32 patients. Results Onset of disease was generally early in life (median age, 6 weeks). The most common symptoms were muscle weakness, hypotonia, and developmental delay/intellectual disability. Nonneurologic symptoms were frequent. Disease causing mutations were found in 20 different nuclear genes, and 7 patients had mutations in mitochondrial DNA. Causative variants were found in 18 of the 32 patients subjected to WES/WGS. Interestingly, many patients had low levels of coEnzyme Q10 in muscle, irrespective of genetic cause. Conclusions Children with combined Enzyme defects display a diversity of clinical symptoms with varying age of presentation. We established the genetic diagnosis in 35 of the 55 patients (64%). The high diagnostic yield was achieved by the introduction of massive parallel sequencing, which also revealed novel genes and enabled elucidation of new disease mechanisms.

  • clinical presentation genetic etiology and coEnzyme q10 levels in 55 children with combined Enzyme Deficiencies of the mitochondrial respiratory chain
    The Journal of Pediatrics, 2021
    Co-Authors: Karin Naess, Helene Bruhn, Henrik Stranneheim, Christoph Freyer, Rolf Wibom
    Abstract:

    Abstract Objectives To evaluate the clinical symptoms, biochemical findings and establish the genetic etiology in a cohort of pediatric patients with combined Deficiencies of the mitochondrial respiratory chain complexes. Study design Clinical and biochemical data were collected from 55 children. All patients were subjected to sequence analysis of the entire mitochondrial genome, except when the causative mutations had been identified based on the clinical picture. Whole exome/genome sequencing (WES/WGS) was performed in 32 patients. Results Onset of disease was generally early in life - median age six weeks. Most common symptoms were muscle weakness, hypotonia and developmental delay/intellectual disability. Non-neurological symptoms were frequent. Disease causing mutations were found in 20 different nuclear genes and seven patients had mutations in mitochondrial DNA. Causative variants have, so far, been found in 18 of the 32 patients subjected to WES/WGS. Interestingly, many of the patients, regardless of genetic cause, had low levels of coEnzyme Q10 in muscle. Conclusion Children with combined Enzyme defects display a diversity of clinical symptoms with varying age of presentation. We established the genetic diagnosis in 35 of the 55 patients (64%). The high diagnostic yield was achieved by the introduction of massive parallel sequencing, which also revealed novel genes and enabled elucidation of new disease mechanisms.

Bernard Korzeniewski - One of the best experts on this subject based on the ideXlab platform.

  • influence of substrate activation hydrolysis of atp by first steps of glycolysis and β oxidation on the effect of Enzyme Deficiencies inhibitors substrate shortage and energy demand on oxidative phosphorylation
    Biophysical Chemistry, 2003
    Co-Authors: Bernard Korzeniewski
    Abstract:

    In intact tissues respiratory substrates (glucose, fatty acids) must be activated with the use of ATP before they may be oxidised and used for energy (ATP) production. This activation by product constitutes an example of a typical positive feedback. In the present paper, the influence of substrate activation on the effect of inborn Enzyme Deficiencies, inhibitors, lowered oxygen tension, respiratory fuel shortage and increased energy demand on respiration and ATP synthesis is studied with the aid of the dynamic computer model of oxidative phosphorylation in isolated mitochondria developed previously. Computer simulations demonstrate that, in the case where oxidative phosphorylation in the whole organism is partially inhibited, the necessity of substrate activation can have significant impact on the relationship between the activity of (particular steps of) oxidative phosphorylation (or the value of energy demand) and the respiration rate. Depending on the sensitivity of ATP usage to ATP concentration, substrate activation may either slightly enhance the effect of the decrease in the oxidative phosphorylation activity (increase in energy demand) or may lead to a non-stability and sudden collapse of the respiration rate and phosphorylation potential below (above) a certain threshold value of oxidative phosphorylation activity (energy demand). This theoretical finding suggests a possible causal relationship between the affinity of ATP usage to [ATP] and the tissue specificity of mitochondrial diseases.

  • parallel activation in the atp supply demand system lessens the impact of inborn Enzyme Deficiencies inhibitors poisons or substrate shortage on oxidative phosphorylation in vivo
    Biophysical Chemistry, 2002
    Co-Authors: Bernard Korzeniewski
    Abstract:

    A potential kinetic impact of parallel activation of different steps during an increased energy demand on the effect of inborn Enzyme Deficiencies, physiological inhibitors, external poisons and substrate shortage on oxidative phosphorylation was studied in the theoretical way. Numerical simulations were performed with the aid of the previously developed computer model of oxidative phosphorylation. It was demonstrated that the parallel activation mechanism diminishes significantly changes in fluxes and metabolite concentrations occurring at a given degree of inactivation of the system by one of the above-mentioned factors. It was also shown that parallel activation decreases greatly the threshold value of the relative activity of oxidative phosphorylation, below which the oxygen consumption flux and ATP turnover flux become significantly affected. Finally, computer simulations predicted that parallel activation leads to a considerable increase in the apparent affinity of oxidative phosphorylation to oxygen, which delays the effect of inhibitors and poisons competing with oxygen for the active centre of cytochrome oxidase. It is concluded that one of possible functions of parallel direct activation of different steps of oxidative phosphorylation is to increase the resistance of the system to a decrease in the concentration/activity of different oxidative phosphorylation complexes.

  • Effect of Enzyme Deficiencies on oxidative phosphorylation: from isolated mitochondria to intact tissues. Theoretical studies.
    Molecular biology reports, 2002
    Co-Authors: Bernard Korzeniewski
    Abstract:

    The present article briefly summarizes the theoretical studies made by the authors and co-workers on the effect of inborn Enzyme Deficiencies on oxidative phosphorylation in intact tissues and on the genesis of mitochondrial diseases. The dynamic computer model of oxidative phosphorylation developed previously allowed to extrapolate experimental data (especially: threshold curves describing the dependence of oxygen consumption and ATP turnover on activities/concentrations of particular oxidative phosphorylation Enzymes) obtained for isolated muscle mitochondria in state 3 at saturating oxygen concentrations to more physiological conditions prevailing in intact tissues. In particular, theoretical studies demonstrated that the threshold value of the relative activity/concentration of a given mitochondrial complex, below which a significant decrease in the respiration rate takes place, increases with an increase in energy demand. This fact was proposed as a possible explanation of the tissue specificity of mitochondrial diseases. Additionally, a decreased oxygen concentration was shown to increase the threshold value (and flux control coefficient) for cytochrome oxidase. We subsequently developed a model called 'binary mitochondria heteroplasmy', in which there are only two subpopulations of mitochondria: one 'wild-type' and one containing only defected molecules of a given Enzyme. In this model we show that a defect has a pronounced effect on oxidative phosphorylation, significantly increasing the threshold value. It was also proposed that a parallel activation in the ATP supply-demand system during an increased energy demand significantly lessens the effect of Enzyme Deficiencies on oxidative phosphorylation (decreases the threshold value). Finally, the necessity of substrate activation may lead to an instability in the system and to appearance of a second threshold, below which respiration suddenly drops to zero, which is equivalent to the energetic death of a cell.