3697G&gt;A in MT-ND1 is a causative mutation in mitochondrial disease

Spangenberg, Lucía; Graña, Martín; Greif, Gonzalo; Suárez-Rivero, Juan M.; Krysztal, Karina; Tapié, Alejandra; Boidi, María; Fraga, Valeria; Lemes, Aída; Gueçaimburú, Rosario; Cerisola, Alfredo; Sánchez-Alcázar, José A.; Robello, Carlos; Raggio, Víctor; Naya, Hugo

doi:10.1016/j.mito.2016.03.006

Cited by 13 publications

(4 citation statements)

References 24 publications

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“…The codifying mtDNA genes as mitochondrial encoded ND genes MTND (1-6) can interfere in complex I electron pumping and therefore produce a compatible phenotype. MTND1 m.3697G > A previously reported in MELAS is suggested to be implied as well [27]. Ma YY.…”

Section: Oxphos Defectssupporting

confidence: 59%

Molecular basis of Leigh syndrome: a current look

Baldo

Vilarinho

2020

Orphanet J Rare Dis

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Leigh Syndrome (OMIM 256000) is a heterogeneous neurologic disorder due to damage in mitochondrial energy production that usually starts in early childhood. The first description given by Leigh pointed out neurological symptoms in children under 2 years and premature death. Following cases brought some hypothesis to explain the cause due to similarity to other neurological diseases and led to further investigation for metabolic diseases. Biochemical evaluation and specific metabolic profile suggested impairment in energy production (OXPHOS) in mitochondria. As direct approach to involved tissues is not always possible or safe, molecular analysis is a great cost-effective option and, besides biochemical results, is required to confirm the underlying cause of this syndrome face to clinical suspicion. The Next Generation Sequencing (NGS) advance represented a breakthrough in molecular biology allowing simultaneous gene analysis giving short-time results and increasing the variants underlying this syndrome, counting over 75 monogenic causes related so far. NGS provided confirmation of emerging cases and brought up diagnosis in atypical presentations as late-onset cases, which turned Leigh into a heterogeneous syndrome with variable outcomes. This review highlights clinical presentation in both classic and atypical phenotypes, the investigation pathway throughout confirmation emphasizing the underlying genetic heterogeneity and increasing number of genes assigned to this syndrome as well as available treatment.

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Section: Oxphos Defectssupporting

confidence: 59%

Molecular basis of Leigh syndrome: a current look

Baldo

Vilarinho

2020

Orphanet J Rare Dis

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“…The remaining genes contain information related with the translational machinery of the mitochondrial genome. , In the nucleus are encoded the genes responsible for the control of mitochondria. Although accounting for only 1% of total DNA, mutations in this genome have been linked to a large variety of metabolic and neuromuscular degenerative syndromes that involves tissues requiring high levels of energy, such as the heart and the brain, and the endocrine and nervous systems. , Mutations involving complex-I-encoding genes frequently cause mitochondrial disorders characterized by diverse clinical phenotypes related with severe childhood metabolic dysfunctions, such as progressive cardiomyopathy, encephalopathy, leukodystrophy, Leigh syndrome, or ragged red fibers syndrome, and premature age-related symptoms. − Furthermore, mutations and/or the great polymorphism occurrence in complex I genes are associated with Parkinson and Alzheimer’s diseases, diabetes, and even the propensity for cancer. − …”

Section: Introductionmentioning

confidence: 99%

Mitochondrial Gene Therapy: Advances in Mitochondrial Gene Cloning, Plasmid Production, and Nanosystems Targeted to Mitochondria

et al. 2017

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Mitochondrial gene therapy seems to be a valuable and promising strategy to treat mitochondrial disorders. The use of a therapeutic vector based on mitochondrial DNA, along with its affinity to the site of mitochondria, can be considered a powerful tool in the reestablishment of normal mitochondrial function. In line with this and for the first time, we successfully cloned the mitochondrial gene ND1 that was stably maintained in multicopy pCAG-GFP plasmid, which is used to transform E. coli. This mitochondrial-gene-based plasmid was encapsulated into nanoparticles. Furthermore, the functionalization of nanoparticles with polymers, such as cellulose or gelatin, enhances their overall properties and performance for gene therapy. The fluorescence arising from rhodamine nanoparticles in mitochondria and a fluorescence microscopy study show pCAG-GFP-ND1-based nanoparticles' cell internalization and mitochondria targeting. The quantification of GFP expression strongly supports this finding. This work highlights the viability of gene therapy based on mitochondrial DNA instigating further in vitro research and clinical translation.

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“…Without affecting the formation of other supercomplexes, the m.3697G>A mutation, which is known to be associated with Leigh’s disease, induced decreased mitochondrial respiration and ATP production, as well as increased ROS and lactate levels. This is, to our knowledge, the first report describing the mechanism of m.3697G>A in mitochondrial disease, although the mutation in mitochondrial disease has been reported in several studies [ 26 , 28 , 36 ]. Given the functional importance of the LSC In + IIIn + IVn, in addition to our findings that the composition of the LSC is variable in different cell types, we propose that mitochondria lacking In + IIIn + IVn LSC contribute to the metabolic shift in different cell models.…”

Section: Discussionmentioning

confidence: 84%

“…m.3697G>A has been linked to Leigh syndrome in a few studies [ 26 , 28 ]. However, how m.3697G>A impairs OXPHOS function is unknown.…”

Section: Resultsmentioning

confidence: 99%

Cell Type-Specific Modulation of Respiratory Chain Supercomplex Organization

Sun

Qiu

et al. 2016

IJMS

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Respiratory chain complexes are organized into large supercomplexes among which supercomplex In + IIIn + IVn is the only one that can directly transfer electrons from NADH to oxygen. Recently, it was reported that the formation of supercomplex In + IIIn + IVn in mice largely depends on their genetic background. However, in this study, we showed that the composition of supercomplex In + IIIn + IVn is well conserved in various mouse and human cell lines. Strikingly, we found that a minimal supercomplex In + IIIn, termed “lowest supercomplex” (LSC) in this study because of its migration at the lowest position close to complex V dimers in blue native polyacrylamide gel electrophoresis, was associated with complex IV to form a supercomplex In + IIIn + IVn in some, but not all of the human and mouse cells. In addition, we observed that the 3697G>A mutation in mitochondrial-encoded NADH dehydrogenase 1 (ND1) in one patient with Leigh’s disease specifically affected the assembly of supercomplex In + IIIn + IVn containing LSC, leading to decreased cellular respiration and ATP generation. In conclusion, we showed the existence of LSC In + IIIn + IVn and impairment of this supercomplex causes disease.

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3697G>A in MT-ND1 is a causative mutation in mitochondrial disease

Cited by 13 publications

References 24 publications

Molecular basis of Leigh syndrome: a current look

Molecular basis of Leigh syndrome: a current look

Mitochondrial Gene Therapy: Advances in Mitochondrial Gene Cloning, Plasmid Production, and Nanosystems Targeted to Mitochondria

Cell Type-Specific Modulation of Respiratory Chain Supercomplex Organization

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