Histidine-450 Is the Catalytic Residue ofl-3-Hydroxyacyl Coenzyme A Dehydrogenase Associated with the Large α-Subunit of the Multienzyme Complex of Fatty Acid Oxidation fromEscherichia coli†

Abstract Medium- and short-chain L-3-hydroxyacyl-coenzyme A dehydrogenase (M/SCHAD, SCHAD) deficiency is a mitochondrial fatty acid oxidation disorder (FAOD). This enzyme catalyzes the penultimate step in fatty acid oxidation, the NAD+ dependent conversion of L-3-hydroxyacyl-CoA to 3-ketoacyl-CoA for medium- and short-chain acyl-CoA intermediates (C4-C12). The clinical presentations of most patients are recurrent hypoglycemia associated with hyperinsulinism. We presented four infants with C4 acyl-carnitine elevation identified by newborn screening that also showed an unusual phenotype of congenital hypotonia and gross developmental delay. Enzymatic studies confirmed the disease. Sequencing analysis of all the HADH coding exons on the four patients revealed a homozygous variant of a novel change (c.908G>T, p.Gly303Val). Western blot analysis subsequently confirmed the lack of the SCHAD protein. In addition, there is another previously reported benign variant (c.257T>C) identified in three infants. Therefore, we postulate that the HADH variant (c.908G>T) is indeed pathogenic and associated with a severe phenotype as evidenced by the cases described herein. Population screening for the c.908G>T mutation suggests this mutation to be common among Puerto Ricans. We recommend that SCHAD deficiency is included as part of the differential diagnosis of all infants with congenital hypotonia.

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Control of mitochondrial gene expression in the aging rat myocardium

Biochemistry and Cell Biology ◽

10.1139/o05-169 ◽

2006 ◽

Vol 84 (2) ◽

pp. 191-198 ◽

Cited By ~ 12

Author(s):

Christophe M.R LeMoine ◽

Grant B McClelland ◽

Carrie N Lyons ◽

Odile Mathieu-Costello ◽

Christopher D Moyes

Keyword(s):

Fatty Acid ◽

Fatty Acid Oxidation ◽

Transcriptional Regulators ◽

Acid Oxidation ◽

Mitochondrial Enzymes ◽

Mrna Levels ◽

Α Subunit ◽

Transcript Levels ◽

Nuclear Respiratory Factor ◽

Age Dependent

Aging induces complex changes in myocardium bioenergetic and contractile properties. Using F344BNF1rats, we examined age-dependent changes in myocardial bioenergetic enzymes (catalytic activities and transcript levels) and mRNA levels of putative transcriptional regulators of bioenergetic genes. Very old rats (35 months) showed a 22% increase in ventricular mass with no changes in DNA or RNA per gram. Age-dependent cardiac hypertrophy was accompanied by complex changes in mitochondrial enzymes. Enzymes of the Krebs cycle and electron transport system remained within 15% of the values measured in adult heart, significant decreases occurring in citrate synthase (10%) and aconitase (15%). Transcripts for these enzymes were largely unaffected by aging, although mRNA levels of putative transcriptional regulators of the enzymes (nuclear respiratory factor (NRF) 1 and 2 α subunit) increased by about 30%–50%. In contrast, enzymes of fatty acid oxidation exhibited a more diverse pattern, with a 50% decrease in β-hydroxyacyl-CoA dehydrogenase (HOAD) and no change in long-chain acyl-CoA dehydrogenase or carnitine palmitoyltransferase. Transcript levels for fatty acid oxidizing enzymes covaried with HOAD, which declined significantly by 30%. There were no significant changes in the relative transcript levels of regulators of genes for fatty acid oxidizing enzymes: peroxisome proliferator-activated receptor-α (PPARα), PPARβ, or PPARγ coactivator-1α (PGC-1α). There were no changes in the mRNA levels of Sirt1, a histone-modifying enzyme that interacts with PGC-1α. Collectively, these data suggest that aging causes complex changes in the enzymes of myocardial energy metabolism, triggered in part by NRF-independent pathways as well as post-transcriptional regulation.Key words: PGC-1a, fatty acid oxidation, nuclear respiratory factor (NRF), PPAR, coactivator, transcriptional regulation.

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