scholarly journals Diminished synthesis of subunit a (ATP6) and altered function of ATP synthase and cytochrome c oxidase due to the mtDNA 2 bp microdeletion of TA at positions 9205 and 9206

2004 ◽  
Vol 383 (3) ◽  
pp. 561-571 ◽  
Author(s):  
Pavel JEŠINA ◽  
Markéta TESAŘOVÁ ◽  
Daniela FORNŮSKOVÁ ◽  
Alena VOJTÍŠKOVÁ ◽  
Petr PECINA ◽  
...  
Keyword(s):  
Cytochrome C ◽  
Cytochrome C Oxidase ◽  
Atp Synthase ◽  
Stop Codon ◽  
Atp Synthesis ◽  
Pcr Analysis ◽  
Mitochondrial Atpase ◽  
Atpase Subunit ◽  
Mitochondrial Encephalomyopathies ◽  
Subunit A

Dysfunction of mitochondrial ATPase (F1Fo-ATP synthase) due to missense mutations in ATP6 [mtDNA (mitochondrial DNA)-encoded subunit a] is a frequent cause of severe mitochondrial encephalomyopathies. We have investigated a rare mtDNA mutation, i.e. a 2 bp deletion of TA at positions 9205 and 9206 (9205ΔTA), which affects the STOP codon of the ATP6 gene and the cleavage site between the RNAs for ATP6 and COX3 (cytochrome c oxidase 3). The mutation was present at increasing load in a three-generation family (in blood: 16%/82%/>98%). In the affected boy with severe encephalopathy, a homoplasmic mutation was present in blood, fibroblasts and muscle. The fibroblasts from the patient showed normal aurovertin-sensitive ATPase hydrolytic activity, a 70% decrease in ATP synthesis and an 85% decrease in COX activity. ADP-stimulated respiration and the ADP-induced decrease in the mitochondrial membrane potential at state 4 were decreased by 50%. The content of subunit a was decreased 10-fold compared with other ATPase subunits, and [35S]-methionine labelling showed a 9-fold decrease in subunit a biosynthesis. The content of COX subunits 1, 4 and 6c was decreased by 30–60%. Northern Blot and quantitative real-time reverse transcription–PCR analysis further demonstrated that the primary ATP6 – COX3 transcript is cleaved to the ATP6 and COX3 mRNAs 2–3-fold less efficiently. Structural studies by Blue-Native and two-dimensional electrophoresis revealed an altered pattern of COX assembly and instability of the ATPase complex, which dissociated into subcomplexes. The results indicate that the 9205ΔTA mutation prevents the synthesis of ATPase subunit a, and causes the formation of incomplete ATPase complexes that are capable of ATP hydrolysis but not ATP synthesis. The mutation also affects the biogenesis of COX, which is present in a decreased amount in cells from affected individuals.

Alteration of structure and function of ATP synthase and cytochrome c oxidase by lack of Fo-a and Cox3 subunits caused by mitochondrial DNA 9205delTA mutation

2015 ◽  
Vol 466 (3) ◽  
pp. 601-611 ◽  
Author(s):  
Kateřina Hejzlarová ◽  
Vilma Kaplanová ◽  
Hana Nůsková ◽  
Nikola Kovářová ◽  
Pavel Ješina ◽  
...  
Keyword(s):  
Cytochrome C ◽  
Cytochrome C Oxidase ◽  
Atp Synthase ◽  
Stop Codon ◽  
Threshold Effect ◽  
Structure And Function ◽  
Missense Mutations ◽  
Atp Production ◽  
Atp6 Gene ◽  
And Function

Mutations in the MT-ATP6 gene are frequent causes of severe mitochondrial disorders. Typically, these are missense mutations, but another type is represented by the 9205delTA microdeletion, which removes the stop codon of the MT-ATP6 gene and affects the cleavage site in the MT-ATP8/MT-ATP6/MT-CO3 polycistronic transcript. This interferes with the processing of mRNAs for the Atp6 (Fo-a) subunit of ATP synthase and the Cox3 subunit of cytochrome c oxidase (COX). Two cases described so far presented with strikingly different clinical phenotypes–mild transient lactic acidosis or fatal encephalopathy. To gain more insight into the pathogenic mechanism, we prepared 9205delTA cybrids with mutation load ranging between 52 and 99% and investigated changes in the structure and function of ATP synthase and the COX. We found that 9205delTA mutation strongly reduces the levels of both Fo-a and Cox3 proteins. Lack of Fo-a alters the structure but not the content of ATP synthase, which assembles into a labile, ∼60 kDa smaller, complex retaining ATP hydrolytic activity but which is unable to synthesize ATP. In contrast, lack of Cox3 limits the biosynthesis of COX but does not alter the structure of the enzyme. Consequently, the diminished mitochondrial content of COX and non-functional ATP synthase prevent most mitochondrial ATP production. The biochemical effects caused by the 9205delTA microdeletion displayed a pronounced threshold effect above ∼90% mutation heteroplasmy. We observed a linear relationship between the decrease in subunit Fo-a or Cox3 content and the functional presentation of the defect. Therefore we conclude that the threshold effect originated from a gene–protein level.

Uranium inhibits mammalian mitochondrial cytochrome c oxidase and ATP synthase

2021 ◽  
Vol 271 ◽  
pp. 116377
Author(s):  
Libing Yu ◽  
Wenjing Li ◽  
Jian Chu ◽  
Chun Chen ◽  
Xijian Li ◽  
...  
Keyword(s):  
Cytochrome C ◽  
Cytochrome C Oxidase ◽  
Atp Synthase ◽  
Mitochondrial Cytochrome ◽  
Mitochondrial Cytochrome C

scholarly journals Pathology of Mitochondrial Encephalomyopathies

2005 ◽  
Vol 32 (2) ◽  
pp. 152-166 ◽  
Author(s):  
Harvey B. Sarnat ◽  
José Marín-García
Keyword(s):  
Cytochrome C ◽  
Succinate Dehydrogenase ◽  
Cytochrome C Oxidase ◽  
Oxidase Activity ◽  
Morphological Evidence ◽  
Regular Feature ◽  
Complex Iv ◽  
Genetic Studies ◽  
Mitochondrial Encephalomyopathies ◽  
Mitochondrial Cytopathy

ABSTRACT:Muscle biopsy provides the best tissue to confirm a mitochondrial cytopathy. Histochemical features often correlate with specific syndromes and facilitate the selection of biochemical and genetic studies. Ragged-red fibres nearly always indicate a combination defect of respiratory complexes I and IV. Increased punctate lipid within myofibers is a regular feature of Kearns-Sayre and PEO, but not of MELAS and MERRF. Total deficiency of succinate dehydrogenase indicates a severe defect in Complex II; total absence of cytochrome-c-oxidase activity in all myofibres correlates with a severe deficiency of Complex IV or of coenzyme-Q10. The selective loss of cytochrome-c-oxidase activity in scattered myofibers, particularly if accompanied by strong succinate dehydrogenase staining in these same fibres, is good evidence of mitochondrial cytopathy and often of a significant mtDNA mutation, though not specific for Complex IV disorders. Glycogen may be excessive in ragged-red zones. Ultrastructure provides morphological evidence of mitochondrial cytopathy, in axons and endothelial cells as well as myocytes. Abnormal axonal mitochondria may contribute to neurogenic atrophy of muscle, a secondary chronic feature. Quantitative determinations of respiratory chain enzyme complexes, with citrate synthase as an internal control, confirm the histochemical impressions or may be the only evidence of mitochondrial disease. Biological and technical artifacts may yield falsely low enzymatic activities. Genetic studies screen common point mutations in mtDNA. The brain exhibits characteristic histopathological alterations in mitochondrial diseases. Skin biopsy is useful for mitochondrial ultrastructure in smooth erector pili muscles and axons; skin fibroblasts may be grown in culture. Mitochondrial alterations occur in many nonmitochondrial diseases and also may be induced by drugs and toxins.

Correlations between ATP hydrolysis, ATP synthesis, generation and utilization of ΔpH in mitochondrial ATPase-ATP synthase

1983 ◽  
Vol 725 (3) ◽  
pp. 464-471 ◽  
Author(s):  
Gilbert Deléage ◽  
François Penin ◽  
Catherine Godinot ◽  
Danièle C. Gautheron
Keyword(s):  
Atp Synthase ◽  
Atp Hydrolysis ◽  
Atp Synthesis ◽  
Mitochondrial Atpase

scholarly journals ATP synthesis without R210 of subunit a in the Escherichia coli ATP synthase

2008 ◽  
Vol 1777 (1) ◽  
pp. 32-38 ◽  
Author(s):  
Robert R. Ishmukhametov ◽  
J. Blake Pond ◽  
Asma Al-Huqail ◽  
Mikhail A. Galkin ◽  
Steven B. Vik
Keyword(s):  
Escherichia Coli ◽  
Atp Synthase ◽  
Atp Synthesis ◽  
Subunit A

scholarly journals New insights into mitogenomic phylogeny and copy number in eight indigenous sheep populations based on the ATP synthase and cytochrome c oxidase genes

animal ◽  
2018 ◽  
Vol 12 (7) ◽  
pp. 1341-1349
Author(s):  
P. Xiao ◽  
L.L. Niu ◽  
Q.J. Zhao ◽  
X.Y. Chen ◽  
L.J. Wang ◽  
...  
Keyword(s):  
Cytochrome C ◽  
Cytochrome C Oxidase ◽  
Atp Synthase ◽  
Copy Number ◽  
Indigenous Sheep
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