m.6267G&gt;A: a recurrent mutation in the human mitochondrial DNA that reduces cytochrome c oxidase activity and is associated with tumors

Gallardo, M. Esther; Moreno‐Loshuertos, Raquel; López, Cecilia I.; Casqueiro, Mercedes; Silva, Javier; Bonilla, Félix; Córdoba, Santiago Rodrı́guez de; Enríquez, José Antonio

doi:10.1002/humu.20338

Cited by 56 publications

(33 citation statements)

References 46 publications

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“…Total DNA was isolated from cells by digestion with proteinase K in TE buffer (10 mM Tris, 1 mM EDTA, pH 7.5) containing 0.5% SDS and RNase A, purified by extraction with phenol-chloroform-isoamyl alcohol, and precipitated with ethanol. The complete mtDNA was amplified in 24 overlapping 800-to 1,000-bp-long PCR fragments using a multifunctional robot (Genesis 150 Tecan; Crailsheim) (20). Primers were designed using the reference sequence (NC_005089) (7).…”

Section: Methodsmentioning

confidence: 99%

Five Entry Points of the Mitochondrially Encoded Subunits in Mammalian Complex I Assembly

Perales‐Clemente

Fernández-Vizarra

Acı́n-Pérez

et al. 2010

Molecular and Cellular Biology

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Complex I (CI) is the largest enzyme of the mammalian mitochondrial respiratory chain. The biogenesis of the complex is a very complex process due to its large size and number of subunits (45 subunits). The situation is further complicated due to the fact that its subunits have a double genomic origin, as seven of them are encoded by the mitochondrial DNA. Understanding of the assembly process and characterization of the involved factors has advanced very much in the last years. However, until now, a key part of the process, that is, how and at which step the mitochondrially encoded CI subunits (ND subunits) are incorporated in the CI assembly process, was not known. Analyses of several mouse cell lines mutated for three ND subunits allowed us to determine the importance of each one for complex assembly/stability and that there are five different steps within the assembly pathway in which some mitochondrially encoded CI subunit is incorporated.Complex I (CI) (NADH-ubiquinone oxidoreductase; EC 1.6.5.3) is one of the main electron entry points in the mitochondrial respiratory electron transport chain catalyzing the oxidation of NADH to reduce ubiquinone to ubiquinol (31,39,40), contributing to the proton motive force to synthesize ATP by the process called oxidative phosphorylation (OXPHOS).CI assembly is a difficult problem to address due to the large size of the complex and its dual genomic nature, as 7 out of its 45 subunits are encoded by the mitochondrial DNA (mtDNA) (10, 11). Until very recently, mammalian CI assembly was explained using two different and apparently contradictory models. One model was proposed by following the time course of formation of CI intermediates in human cells in culture once mitochondrial protein synthesis had recovered after its inhibition by doxycycline (36). Based on these observations, human CI was proposed to be assembled through two different modules corresponding to the membrane and peripheral arms. The other model was proposed after analysis of a cohort of four CI-deficient patients in which seven putative assembly intermediates containing a combination of both peripheral-and membrane arm subunits were identified. Thus, an assembly pathway in which the peripheral-and membrane arm subassemblies came together before the completion of each of the arms was proposed (4). However, the most recent studies have refined the previous models and propose an overlapping view of the process. One study, by green fluorescent protein (GFP) tagging of the NDUFS3 subunit, identified six peripheral-arm intermediates. The second and third smaller NDUFS3-containing subassemblies were accumulated and could not advance into higher-molecular-mass species when mitochondrial protein synthesis was inhibited, thus determining the entry point of the mitochondrially encoded subunits in the CI assembly pathway (37). The most recent study analyzed the incorporation of the mitochondrial subunits in a time course to the fully assembled CI and, on the other hand, the incorporation of the nuclear subunits by ...

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Section: Methodsmentioning

confidence: 99%

Five Entry Points of the Mitochondrially Encoded Subunits in Mammalian Complex I Assembly

Perales‐Clemente

Fernández-Vizarra

Acı́n-Pérez

et al. 2010

Molecular and Cellular Biology

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“…Several of the cancer-associated mutations found in mtDNA result in structural modifications of cytochrome c oxidase (CytcO) (9,(13)(14)(15) (Fig. 1A).…”

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A mitochondrial DNA mutation linked to colon cancer results in proton leaks in cytochrome c oxidase

Namslauer

Brzezinski

2009

Proc. Natl. Acad. Sci. U.S.A.

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An increasing number of cancer types have been found to be linked to specific mutations in the mitochondrial DNA, which result in specific structural changes of the respiratory enzyme complexes. In this study, we have investigated the effect of 2 such mutations identified in colon cancer patients, leading to the amino acid substitutions Ser458Pro and Gly125Asp in subunit I of cytochrome c oxidase (complex IV) [Greaves et al. (2006) Proc Natl Acad Sci USA 103:714 -719]. We introduced these mutations in Rhodobacter sphaeroides, which carries an oxidase that serves as a model of the mitochondrial counterpart. The lack of expression of the former variant indicates that the amino acid substitution results in severely altered overall structure of the enzyme. The latter mutation (Gly171Asp in the bacterial oxidase) resulted in a structurally intact enzyme, but with reduced activity (approximately 30%), mainly due to slowed reduction of the redox site heme a. Furthermore, even though the Gly171Asp CytcO pumps protons, an intrinsic proton leak was identified, which would lead to a decreased overall energy-conversion efficiency of the respiratory chain, and would also perturb transport processes such as protein, ion, and metabolite trafficking. Furthermore, the specific leak may act to alter the balance between the electrical and chemical components of the proton electrochemical gradient. cytochrome aa3 ͉ electrochemical ͉ electron transfer ͉ pump ͉ respiratory oxidase

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“…sequence variation may have a functional consequence; (v) this mutation was identified only once in a total of more than 4000 mtDNA sequences from public databases (Ingman and Gyllensten, 2003) and in more than 600 mtDNA sequences from our laboratory, which include controls and samples from a wide spectrum of pathological conditions associated to mitochondrial dysfunctions; and vi) as an indication for suspecting its pathogenic character, the other sample in which the m.1628C>T sequence variation was identified corresponds to a different haplogroup (haplogroup HV) (Torroni et al, 2003;Gallardo et al, 2006;DiMauro, 2011). In consequence, we propose that, in the absence of functional studies, the m.1628C>T transition in the MT-TV gene is a good candidate to be responsible for the clinical phenotype observed in patient 1.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial tRNA valine as a recurrent target for mutations involved in mitochondrial cardiomyopathies

et al. 2012

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m.6267G>A: a recurrent mutation in the human mitochondrial DNA that reduces cytochrome c oxidase activity and is associated with tumors

Cited by 56 publications

References 46 publications

Five Entry Points of the Mitochondrially Encoded Subunits in Mammalian Complex I Assembly

Five Entry Points of the Mitochondrially Encoded Subunits in Mammalian Complex I Assembly

A mitochondrial DNA mutation linked to colon cancer results in proton leaks in cytochrome c oxidase

Mitochondrial tRNA valine as a recurrent target for mutations involved in mitochondrial cardiomyopathies

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