Ndufs4 related Leigh syndrome: A case report and review of the literature

Ortigoza‐Escobar, Juan Darío; Oyarzábal, Alfonso; Montero, Raquel; Artuch, Rafael; Jou, Cristina; Jimenez, Cecilia; Gort, Laura; Briones, Paz; Muchart, Jordi; López‐Gallardo, Ester; Emperador, Sonia; Pesini, Eduardo Ruiz; Montoya, Julio; Pérez, Belén; Rodríguez‐Pombo, Pilar; Pérez‐Dueñas, Belén

doi:10.1016/j.mito.2016.04.001

Cited by 63 publications

(52 citation statements)

References 42 publications

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“…NADH-ubiquinone oxidoreductase is a complex containing 44 subunits. Disassociation or mutation of this complex exists within many human disorders such as Leigh syndrome (14). Of note, pathological defects of mitochondrial respiration have a close correlation with both acute neuronal trauma and chronic neurodegenerative diseases (13).…”

Section: A Series Of Nbp Potential Targets Resulting From Search Are mentioning

confidence: 99%

The novel targets of DL-3-n-butylphthalide predicted by similarity ensemble approach in combination with molecular docking study

Wang

Zhang

et al. 2017

Quant. Imaging Med. Surg.

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Background: DL-3-n-butylphthalide (NBP) is a drug for treating acute ischemic stroke, and may play a neuroprotective role by acting on multiple active targets. The aim of this study was to predict the target proteins of NBP in mammalian cells. Methods:The similarity ensemble approach search tool (SEArch), one of the commonly used public bioinformatics tools for target prediction, was employed in the experiment. The molecular docking of NBP to target proteins was performed by using the three-dimensional (3-D) crystal structure, substrate free. The software AutoDock Vina was used for all dockings. The binding targets of NBP were illustrated as 3-D and 2-D diagrams.Results: Firstly, the results showed that NBP bounded to the same binding site on NAD(P)H quinone oxidoreductases (NQO1) as the substrate FAD, leading to competitive inhibition for the catalytic site with −7.2 kcal/mol. This might break the 3-D structure of NQO1 and bring about P53 degradation, resulting in a decrease of p53-mediated apoptosis in ischemic brain cells. Secondly, NBP might exert its therapeutic effect on acute ischemic stroke via modulating indoleamine 2,3-dioxygenase (IDO) bioactivity after associating with it. NBP could alleviate the depression following ischemic stroke by inhibiting IDO. Thirdly, NBP might modulate the function of NADH-ubiquinone oxidoreductase by competitively embedding itself into this complex, further affecting mitochondrial respiration in cerebrovascular diseases as an anti-oxidant agent.Conclusions: Three potential target proteins of NBP were identified, which may provide a novel aspect for better understanding the protective effects of NBP on the nervous system at the molecular level.

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Section: A Series Of Nbp Potential Targets Resulting From Search Are mentioning

confidence: 99%

The novel targets of DL-3-n-butylphthalide predicted by similarity ensemble approach in combination with molecular docking study

Wang

Zhang

et al. 2017

Quant. Imaging Med. Surg.

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“…The parents were heterozygous for this mutation. Imaging 4 months later revealed an increase in the brainstem signal abnormality, concordant with her clinical deterioration and the natural history of Leigh syndrome . By age 2 years, she was no longer able to stand, crawl or cruise and required a tracheostomy and gastrostomy.…”

Section: Case Reportsmentioning

confidence: 62%

Exploring mTOR inhibition as treatment for mitochondrial disease

Sage‐Schwaede

Engelstad

Salazar

et al. 2019

Ann Clin Transl Neurol

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Leigh syndrome and MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke‐like episodes) are two of the most frequent pediatric mitochondrial diseases. Both cause severe morbidity and neither have effective treatment. Inhibiting the mammalian target of rapamycin (mTOR) pathway has been shown in model mice of Leigh syndrome to extend lifespan and attenuate both the clinical and pathological progression of disease. Based on this observation, we treated two children with everolimus, a rapamycin analogue. The child with Leigh syndrome showed sustained benefit, while the child with MELAS failed to respond and died of progressive disease. We discuss possible mechanisms underlying these disparate responses to mTOR inhibition.

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“…The scarcity and high variability of patients has limited our knowledge on the genetic identity and relative contribution of the affected neuronal populations to the phenotype; thus, a model system with consistent neuropathological features resembling mitochondrial disease is a valuable research tool. We have shown 11,13 that mice lacking the Ndufs4 gene (Ndufs4KO mice) recapitulate the clinical signs of the human disease 9,13 . Ndufs4KO mice present overt lesions predominantly in the brainstem 11,13,29 , but also in the striatum in late stages of the disease 13 .…”

Section: Discussionmentioning

confidence: 99%

“…Mutations affecting the NDUFS4 subunit of mitochondrial Complex I, a key structural component for the assembly, stability and activity of the complex 8 , are commonly associated with a severe, early-onset LS phenotype 9 . Although a late-onset case of LS has been recently reported 10 , prognosis is usually poor and most of the patients die in early childhood 4 .…”

Section: Introductionmentioning

confidence: 99%

Defined neuronal populations drive fatal phenotype in Leigh Syndrome

Bolea

Gella

Sanz

et al. 2019

Preprint

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Dysfunctions of the mitochondrial energy-generating machinery cause a series of progressive, untreatable and usually fatal diseases collectively known as mitochondrial disease. High energyrequiring organs such as the brain are especially affected, leading to developmental delay, ataxia, respiratory failure, hypotonia, seizures and premature death. While neural affectation is a critical component of the pathology, only discrete neuronal populations are susceptible. However, their molecular identity and their contribution to the disease remain unknown. Mice lacking the mitochondrial Complex I subunit NDUFS4 (Ndufs4KO mice) recapitulate the classical signs of Leigh Syndrome (LS), the most common presentation of mitochondrial disease with predominant CNS affectation. Here, we identify the critical role of two genetically-defined neuronal populations driving the fatal phenotype in Ndufs4KO mice. Selective inactivation of Ndufs4 in Vglut2expressing glutamatergic neurons causes brainstem inflammation, motor and respiratory deficits, and early death. On the other hand, Ndufs4 deletion in GABAergic neurons leads to basal ganglia inflammation without motor or respiratory involvement, but accompanied by severe refractory epileptic seizures preceding premature death. These results provide novel insight in the cell typespecific contribution to LS pathology and open new avenues to understand the underlying cellular mechanisms of mitochondrial disease.

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Ndufs4 related Leigh syndrome: A case report and review of the literature

Cited by 63 publications

References 42 publications

The novel targets of DL-3-n-butylphthalide predicted by similarity ensemble approach in combination with molecular docking study

The novel targets of DL-3-n-butylphthalide predicted by similarity ensemble approach in combination with molecular docking study

Exploring mTOR inhibition as treatment for mitochondrial disease

Defined neuronal populations drive fatal phenotype in Leigh Syndrome

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