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Bioenergetics
Published in Michael H. Stone, Timothy J. Suchomel, W. Guy Hornsby, John P. Wagle, Aaron J. Cunanan, Strength and Conditioning in Sports, 2023
Michael H. Stone, Timothy J. Suchomel, W. Guy Hornsby, John P. Wagle, Aaron J. Cunanan
Beta-oxidation is a process of extracting energy from FFA. Beta-oxidation is primarily a function of the mitochondrial trifunctional protein. The MTFP is an enzyme complex associated with the inner mitochondrial membrane, although especially long-chain FA are oxidized in oxidative organelles, the peroxisomes. The peroxisomes use a similar oxidative enzyme group as found in the inner mitochondrial membrane. Free fatty acids undergoing β-oxidation result in the accumulation of acetyl-CoA, and H+. The acetyl-CoA can enter the Krebs cycle and the protons, which are carried to the ETS by nicotinic adenine dinucleotide (NAD) and flavin adenine dinucleotide (FAD), can enter the electron transport system (ETS) (see Figure 2.5). Type I muscle fibers generally contain high concentrations of oxidative enzymes compared to type II, thus the process of FFA oxidation is quite important for these fibers (35, 79). Fat use during exercise becomes increasingly important with duration (108).
Hypoparathyroidism in pediatric patients
Published in Pallavi Iyer, Herbert Chen, Thyroid and Parathyroid Disorders in Children, 2020
Andrew C. Calabria, Michael A. Levine
Several syndromes that arise from deletions in mitochondrial DNA have also been associated with hypoparathyroidism, but the mechanism(s) by which mitochondrial defects affect parathyroid gland development or function are unknown (5). These primary mitochondrial disorders include the Kearns–Sayre syndrome (encephalomyopathy, ophthalmoplegia, retinitis pigmentosa, heart block), the Pearson marrow-pancreas syndrome (sideroblastic anemia, neutropenia, thrombocytopenia, pancreatic dysfunction), and the maternally inherited diabetes and deafness syndrome. Hypoparathyroidism has also been described in patients with the mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome, owing to point mutations in mitochondrial tRNA. In addition, mutations in the mitochondrial trifunctional protein (MTP) that result in either isolated long-chain 3-hydroxy-acyl-coenzyme A dehydrogenase (LCHAD) deficiency or loss of all three MTP enzymatic activities have been associated with hypoparathyroidism in a few unrelated patients. This condition manifests as hypoketotic hypoglycemia, cardiomyopathy, hepatic dysfunction, and developmental delay and is associated with maternal fatty liver of pregnancy. Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) due to mutations in the ACADM gene has also been associated with hypoparathyroidism.
Long-chain L-3-hydroxyacyl-CoA dehydrogenase – (trifunctional protein) deficiency
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop
LCHAD deficiency is transmitted as an autosomal recessive trait. The molecular defect is in the mitochondrial trifunctional protein, which contains activities of LCHAD, 2-enoylCoA hydratase, and 3-oxoacylCoA thiolase. It differs from the trifunctional enzyme found in peroxisomes in structure and function [3], and is capable by itself of catalyzing the three sequential steps of β-oxidation. In some patients, there is defective activity of all three activities of the protein [27], but in most of the patients, deficiency is isolated to LCHAD. Experience with newborn screening is now becoming available from an increasing number of programs worldwide [34]. The spectrum of disorders differs widely between ethnic groups. Incidence calculations from reports from Australia, Germany, and the United States of a total of 5,256,999 newborns give a combined incidence of approximately 1:250,000/1:750,000 newborns for LCAHD/TFP deficiency. Isolated deficiency of the thiolase has only been reported in a single child [9].
Designation of orphan conditions in Europe: regulatory observations and considerations after implementation of regulation 141/2000
Published in Expert Opinion on Orphan Drugs, 2020
Segundo Mariz, Kerstin Westermark, Bruno Sepodes
Although the COMP will often designate a condition under an umbrella term to capture as many subsets of a condition as possible. In some instances, however it has subdivided them according to how they are classified in the public domain. An example are the mucopolysaccharidosis which have been designated by type as described in the literature (Types I, II, III, IV, VI and VII) with each showing clustering of subsequent submissions and positive opinions totaling 34 positive opinions indicating that this is an area of great interest in development. A similar situation exists for mitochondrial disorders where the classification system describes several different disorders such as: mitochondria DNA depletion syndrome, myopathic form, mitochondrial trifunctional protein deficiency, mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (2 designations) and mitochondrial neurogastrointestinal encephalopathy (2 designations) [11]. There are 7 designations in total retrievable for mitochondrial disorders which are classified theoretically as” various” on the EMA website indicating that there is some interest in developing products in what are very difficult conditions to study and treat.
An update on diagnosis and therapy of metabolic myopathies
Published in Expert Review of Neurotherapeutics, 2018
Disorders of the lipid metabolism are classified according to histological criteria into those with lipid depositions on histological investigations and those without lipid depositions. Those with lipid deposition include, for example, primary carnitine deficiency (PCD), multi-acyl-coenzyme-A dehydrogenase deficiency (MADD), and neutral lipid storage disease with myopathy (NLSD-M) (Table 1) [7]. Those without lipid depositions include, for example, carnitine palmitoyl-transferase-2 (CPT-2) deficiency, mitochondrial trifunctional protein deficiency (MTPD), and the very long chain acyl-coenzyme-A dehydrogenase deficiency (VLCAD). Metabolic myopathies due impaired lipid metabolism may be further divided into those with defective transport of fatty acids into mitochondria and those with impaired oxidation of fatty acids (FAODs) within mitochondria. Up to at least 25 enzymes and specific transport proteins in the β-oxidation pathway have been detected of which 18 have been associated with human disease [8]. Half of these may go along with myopathy (Table 1). Recently, mutations in the electron transfer flavoprotein dehydrogenase (ETFDH) have been identified, which go along with either glutaric aciduria or with lipid storage myopathy.
Spermidine rejuvenates T lymphocytes and restores anticancer immunosurveillance in aged mice
Published in OncoImmunology, 2022
Francesca Castoldi, Guido Kroemer, Federico Pietrocola
Because Spd rapidly boosts the mitochondrial activity of naive CD8 T cells, the authors postulate that Spd would directly affect the enzymatic activity of rate-limiting enzymes acting in the FAO pathway. Using Spd-coated magnetic nanoparticles incubated with HeLa cells lysate, Honjo’s team identifies hydroxyl coenzyme A dehydrogenase subunits a and b (HADHA and HADHB, respectively) – two core components of the mitochondrial trifunctional protein (MTC) complex responsible for long-chain fatty acid oxidation – as the main Spd-binding proteins.5 The authors further validate this key finding in intact cells by means of a proximity ligation assay using antibodies targeting Spd and HDAHA/B. By further analyzing the enzymatic kinetics of the HADHA complex, the authors conclude that Spd interacts with HDAHA/B and allosterically activates its enzymatic activities. Due to the fact that the Km value of Spd for the MTP complex (0.4 μM) is significantly lower than the Km of Spd for deoxyhypusine synthase and EP300 – two well-characterized polyamine targets – Honjo’s team suggests that MTP activation would represent the earliest molecular event upon Spd treatment. Importantly, the authors report that Spermine (Spm) competitively inhibits the FAO-stimulating effect of Spd, suggesting that Spd/Spm ratio may dictate the outcome of cellular responses after Spd treatment. Finally, Honjo’s team utilizes a mouse model in which HADHA expression is conditionally blunted in T cells to confirm that the immunostimulatory effect of SPD+ αPD-L1 combination in young mice relies upon functional HADHA in T cells.5