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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
The LCHAD enzyme is a component of the trifunctional protein (TFP) bound to the inner mitochondrial membrane [3, 4]. The protein is an octamer with two distinct α and β subunits coded for by the HADHA and HADHB genes. Its three activities are long-chain 2-enoylCoA hydratase, LCHAD, and long-chain 3-oxoacylCoA thiolase (LCKAT). The first two enzymatic steps (dehydrogenase and hydratase) reside in the α-subunit and the thiolase activity in the β-subunit. LCHAD activity against 3-hydroxyacyl CoA substrates is optimal for compounds of C12–C16 chain length, in contrast to the short-chain-3-hydroacylCoA dehydrogenase (SCHAD), where specificity is optimal at C6. LCHAD action is highest at C16 and inactive at C4. The thiolase and enoyl hydrolase activities also have long-chain specificities. The LCHAD enzyme catalyzes the reversible dehydration of the 3-hydroxy group to a 3-keto group, and nicotine adenine dinucleotide (NAD) is the hydrogen acceptor (Figure 41.1). Patients with LCHAD deficiency may be deficient in LCHAD activity specifically, or may be deficient in all three activities of the TFP. The genes for the α- and β-subunits have been cloned [5]. The α-cDNA codes for an 82,598 Da precursor of a mature 78,969 Da protein. In mitochondrial trifunctional protein (MTP) deficiency, all three activities, dehydrogenase, hydratase, and this thiolase are deficient [6]. Mutational analysis has revealed a number of distinct mutations including one that appears to be common, a G1528C point mutation in the dehydrogenase coding region that changes a glutamic acid to a glutamine [6, 7]. Isolated deficiency of LCHAD is coded for by specific mutations in the HADHA gene, especially the common G1528C point mutation [8]. Isolated deficiency of LCKAT activity has been reported once caused by a mutation (F431S) in the HADHB gene [9]. Generalized TFP deficiency can result from heterogeneous mutations in either the alpha-subunit or the beta-subunit of the TFP.
Trimetazidine ameliorates sunitinib-induced cardiotoxicity in mice via the AMPK/mTOR/autophagy pathway
Published in Pharmaceutical Biology, 2019
Yi Yang, Na Li, Tongshuai Chen, Chunmei Zhang, Lingxin Liu, Yan Qi, Peili Bu
Trimetazidine (TMZ) is a conventionally used drug for angina pectoris. TMZ acts by selectively inhibiting mitochondrial long-chain 3-ketoacyl-CoA thiolase (HADHA), a key enzyme for the β-oxidation of fatty acids, and in turn, inhibits β-oxidation of fatty acids and promotes glucose utilization, improving cardiac energy metabolism (Lopatin et al. 2016). Although primarily used for coronary artery diseases, TMZ has also shown cardioprotective effects in a range of other cardiovascular diseases, including non-ischemic cardiomyopathy, sepsis, anticancer drug-induced cardiotoxicity, diabetic cardiomyopathy and contrast-induced nephropathy (Zou et al. 2017). To date, TMZ efficacy in anticancer drug-induced cardiotoxicity has mainly focused on anthracycline-induced cardiotoxicity. TMZ has been demonstrated to impede anthracycline-induced lipid peroxidation and inflammation and exert cardioprotective effects (Tallarico et al. 2003; Mele et al. 2016). Nevertheless, SU injures the myocardium via mechanisms different from anthracyclines, and potential effects of TMZ in SU-induced cardiotoxicity have not been investigated.
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
Retained visual function in a subset of patients with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD)
Published in Ophthalmic Genetics, 2021
Simon Dulz, Yevgeniya Atiskova, Peter Engel, Jan Wildner, Konstantinos Tsiakas, Rene Santer
Six patients with genetically verified LCHADD were included. Three of these patients (A1-A3) were detected by newborn screening established in 2001 at our institution, three patients (A4-A6) were diagnosed within the first year of life due to metabolic derailment and recurrent rhabdomyolysis. The diagnosis was verified by genetic analyses in all cases: five of them were homozygous for the HADHA c.1528 G > C variant and one patient was not further identified compound heterozygous mutation. In all of them, a permanent low-fat diet including the supplementation of essential fatty acids was initiated at the time of diagnosis and strict adherence to therapy was only observed in patient A6.