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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
In two unrelated patients, mutations were found for the first time in the HADHB gene [44]. In a French cohort of 52 patients with mitochondrial trifunctional protein deficiency, the majority of identified mutations generated premature termination codons resulting in nonsense mRNA-mediated decay [6]. It appears that both normal α and β are important for stabilization of the trifunctional protein. Lethal disease was reported in a case of uniparental disomy of chromosome 2 leading to homozygous mutation in HADHA [45]. A knock-out mouse lacking the α and β subunits of MTP has neonatal hypoglycemia and sudden death [46].
Effects of psychoactive drugs on cellular bioenergetic pathways
Published in The World Journal of Biological Psychiatry, 2021
Chiara C. Bortolasci, Briana Spolding, Srisaiyini Kidnapillai, Mark F. Richardson, Nina Vasilijevic, Sheree D. Martin, Laura J. Gray, Sean L. McGee, Michael Berk, Ken Walder
While none of the drugs had overall significant effects on the expression of genes involved in glycolysis or fatty acid beta oxidation, quetiapine increased the expression of the glycolytic enzyme genes GPI (q = 0.017), ALDOC (q = 8.2E-08) and ENO2 (q = 3.0E-50) and decreased the expression of PGK1 (q = 0.000013) in NT2-N cells. Quetiapine also reduced the expression of genes involved in fatty acid oxidation in NT2-N cells including ECHS1 (q = 0.000013), HADHB (q = 0.0010) and ACAT1 (q = 0.00031). Valproate also had mixed effects on genes involved in glycolysis, increasing the expression of PFKP (q = 0.00017) and ALDOC (q = 0.047), and decreasing the expression of ALDOA (q = 0.000029), GAPDH (q = 2.3E-05), ENO1 (q = 0.0096) and PKM (q = 3.0E-07) in NT2-N cells. There were no significant effects of any of the drugs in C8-B4 cells. None of the drugs significantly affected glycolysis, as measured by extracellular acidification rate, in either cell type (Figures 8 and 9).
Proteomic study of skeletal muscle in obesity and type 2 diabetes: progress and potential
Published in Expert Review of Proteomics, 2018
In the latest attempt to characterize T2D-related alterations in the skeletal muscle proteome, Giebelstein et al. took advantage of protein separation and quantification by 2D-DIGE and protein identification using nano-HPLC/ESI-MS/MS to compare the skeletal muscle proteome of patients with T2D with healthy lean and obese non-diabetic individuals [64]. In this study, 25 proteins were found to be at least 1.5-fold and significantly (p < 0.05) altered in T2D and/or obesity versus lean individuals in either the basal or insulin-stimulated state. The abundance of multiple glycolytic proteins (GAPDH, PGAM2, ENO3, PKM2) and fast muscle protein isoforms (MYL1, MYLPF, TNNT3) was higher in obese non-diabetic individuals and patients with T2D when compared with the lean non-diabetic individuals. Consistent with these findings, the abundance of most protein spots containing glycolytic enzymes and fast muscle protein isoforms correlated negatively with the insulin-stimulated glucose disposal rate and glucose oxidation, while correlating positively with insulin-stimulated lipid oxidation. In contrast to the glycolytic proteins, proteins involved in mitochondrial functions (ECH1, GBAS, HADHB, HES1) and slow muscle protein isoforms (MYL2, MYL3, TNNT1) showed reduced abundance in the insulin-resistant groups. The abundance of these proteins and other mitochondrial proteins involved in the TCA cycle and mitochondrial respiration correlated positively with the insulin-stimulated glucose disposal rate and/or the non-oxidative glucose metabolism.
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