scholarly journals Steroidogenic electron-transfer factors and their diseases

2021 ◽  
Vol 26 (3) ◽  
pp. 138-148
Author(s):  
Walter L. Miller
Keyword(s):  
Electron Transfer ◽  
Cytochrome B5 ◽  
Friedreich Ataxia ◽  
Mitochondrial Diseases ◽  
Transfer Factors ◽  
Skeletal Malformation ◽  
Genital Ambiguity ◽  
Genes Encoding ◽  
Electron Donation ◽  
Por Deficiency

Most steroidogenesis disorders are caused by mutations in genes encoding the steroidogenic enzymes, but work in the past 20 years has identified related disorders caused by mutations in the genes encoding the cofactors that transport electrons from NADPH to P450 enzymes. Most P450s are microsomal and require electron donation by P450 oxidoreductase (POR); by contrast, mitochondrial P450s require electron donation via ferredoxin reductase (FdxR) and ferredoxin (Fdx). POR deficiency is the most common and best-described of these new forms of congenital adrenal hyperplasia. Severe POR deficiency is characterized by the Antley-Bixler skeletal malformation syndrome and genital ambiguity in both sexes, and hence is easily recognized, but mild forms may present only with infertility and subtle disorders of steroidogenesis. The common POR polymorphism A503V reduces catalysis by P450c17 (17-hydroxylase/17,20-lyase) and the principal drugmetabolizing P450 enzymes. The 17,20-lyase activity of P450c17 requires the allosteric action of cytochrome b5, which promotes interaction of P450c17 with POR, with consequent electron transfer. Rare b5 mutations are one of several causes of 17,20-lyase deficiency. In addition to their roles with steroidogenic mitochondrial P450s, Fdx and FdxR participate in the synthesis of iron-sulfur clusters used by many enzymes. Disruptions in the assembly of Fe-S clusters is associated with Friedreich ataxia and Parkinson disease. Recent work has identified mutations in FdxR in patients with neuropathic hearing loss and visual impairment, somewhat resembling the global neurologic disorders seen with mitochondrial diseases. Impaired steroidogenesis is to be expected in such individuals, but this has not yet been studied.

scholarly journals Electron transfer by human wild-type and A287P mutant P450 oxidoreductase assessed by transient kinetics: functional basis of P450 oxidoreductase deficiency

2015 ◽  
Vol 468 (1) ◽  
pp. 25-31 ◽  
Author(s):  
Yi Jin ◽  
Mo Chen ◽  
Trevor M. Penning ◽  
Walter L. Miller
Keyword(s):  
Electron Transfer ◽  
European Ancestry ◽  
Wild Type ◽  
Transient Kinetics ◽  
Skeletal Malformation ◽  
P450 Oxidoreductase ◽  
Sex Development ◽  
Cytochrome P450 Oxidoreductase ◽  
Flavin Binding ◽  
Human Wild Type

We show that the cytochrome P450 oxidoreductase (POR) A287P variant, which can lead to skeletal malformation and disordered sex development, found in 40% of patients of European ancestry is characterized by deficient flavin binding and impaired electron transfer from NADPH.

scholarly journals Mitochondrial Protein Translation: Emerging Roles and Clinical Significance in Disease

2021 ◽  
Vol 9 ◽  
Author(s):  
Fei Wang ◽  
Deyu Zhang ◽  
Dejiu Zhang ◽  
Peifeng Li ◽  
Yanyan Gao
Keyword(s):  
Ribosomal Proteins ◽  
Large Fraction ◽  
Mitochondrial Protein ◽  
Mitochondrial Diseases ◽  
Protein Translation ◽  
Genetic System ◽  
Mitochondrial Rna ◽  
Trna Synthetases ◽  
Translation Factors ◽  
Genes Encoding

Mitochondria are one of the most important organelles in cells. Mitochondria are semi-autonomous organelles with their own genetic system, and can independently replicate, transcribe, and translate mitochondrial DNA. Translation initiation, elongation, termination, and recycling of the ribosome are four stages in the process of mitochondrial protein translation. In this process, mitochondrial protein translation factors and translation activators, mitochondrial RNA, and other regulatory factors regulate mitochondrial protein translation. Mitochondrial protein translation abnormalities are associated with a variety of diseases, including cancer, cardiovascular diseases, and nervous system diseases. Mutation or deletion of various mitochondrial protein translation factors and translation activators leads to abnormal mitochondrial protein translation. Mitochondrial tRNAs and mitochondrial ribosomal proteins are essential players during translation and mutations in genes encoding them represent a large fraction of mitochondrial diseases. Moreover, there is crosstalk between mitochondrial protein translation and cytoplasmic translation, and the imbalance between mitochondrial protein translation and cytoplasmic translation can affect some physiological and pathological processes. This review summarizes the regulation of mitochondrial protein translation factors, mitochondrial ribosomal proteins, mitochondrial tRNAs, and mitochondrial aminoacyl-tRNA synthetases (mt-aaRSs) in the mitochondrial protein translation process and its relationship with diseases. The regulation of mitochondrial protein translation and cytoplasmic translation in multiple diseases is also summarized.

Electron-transfer self-exchange kinetics of cytochrome b5

1990 ◽  
Vol 112 (3) ◽  
pp. 1082-1088 ◽  
Author(s):  
Dabney White Dixon ◽  
Xiaole Hong ◽  
Scott E. Woehler ◽  
A. Grant Mauk ◽  
Bhavini P. Sishta
Keyword(s):  
Electron Transfer ◽  
Cytochrome B5 ◽  
Exchange Kinetics ◽  
Kinetics Of

The heart in neuromuscular disease: primary mitochondrial diseases

ESC CardioMed ◽  
2018 ◽  
pp. 1528-1530
Author(s):  
Denis Duboc
Keyword(s):  
Neuromuscular Disease ◽  
Nuclear Dna ◽  
Single Cells ◽  
Mitochondrial Diseases ◽  
Respiratory Chain Complexes ◽  
Base Pairs ◽  
Daughter Cells ◽  
Dna Molecule ◽  
Chain Complexes ◽  
Genes Encoding

Mitochondria are responsible for energy production in most eukaryotic cells. Each cell contains at least one mitochondrion and every mitochondrion contains two to ten copies of a circular DNA molecule (mitochondrial DNA or mtDNA). Cardiomyocytes contain approximately 10,000 mtDNA copies. MtDNA is composed of around 16,500 base pairs and 37 genes encoding 13 subunits of the respiratory chain complexes I, III, IV, and V, 22 mitochondrial tRNAs and 2 rRNAs. With each cell division, mitochondria and mtDNA are randomly distributed to daughter cells. In humans, mitochondria are inherited exclusively from the mother. In healthy people mtDNA copies are usually identical at birth (homoplasmy) but with ageing, mtDNA is particularly prone to somatic mutation because, unlike nuclear DNA, it is continuously replicated, even in non-dividing tissues such as myocardium. This can lead to the propagation of somatic mutations within single cells by a process called clonal expansion. In addition, mtDNA lacks an extensive DNA repair mechanism.

scholarly journals Accelerated Electro-Fermentation of Acetoin in Escherichia coli by Identifying Physiological Limitations of the Electron Transfer Kinetics and the Central Metabolism

2020 ◽  
Vol 8 (11) ◽  
pp. 1843
Author(s):  
Sebastian Beblawy ◽  
Laura-Alina Philipp ◽  
Johannes Gescher
Keyword(s):  
Escherichia Coli ◽  
Electron Transfer ◽  
Point Mutations ◽  
Selective Adaptation ◽  
Space Time ◽  
Transport Chain ◽  
Whole Cell Biocatalyst ◽  
Genes Encoding ◽  
Space Time Yield ◽  
Respiratory Conditions

Anode-assisted fermentations offer the benefit of an anoxic fermentation routine that can be applied to produce end-products with an oxidation state independent from the substrate. The whole cell biocatalyst transfers the surplus of electrons to an electrode that can be used as a non-depletable electron acceptor. So far, anode-assisted fermentations were shown to provide high carbon efficiencies but low space-time yields. This study aimed at increasing space-time yields of an Escherichia coli-based anode-assisted fermentation of glucose to acetoin. The experiments build on an obligate respiratory strain, that was advanced using selective adaptation and targeted strain development. Several transfers under respiratory conditions led to point mutations in the pfl, aceF and rpoC gene. These mutations increased anoxic growth by three-fold. Furthermore, overexpression of genes encoding a synthetic electron transport chain to methylene blue increased the electron transfer rate by 2.45-fold. Overall, these measures and a medium optimization increased the space-time yield in an electrode-assisted fermentation by 3.6-fold.

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