Mutations in mitochondrially encoded complex I enzyme as the second common cause in a cohort of Chinese patients with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes

Zhao, Danhua; Hong, Daojun; Zhang, Wei; Yao, Sheng; Qi, Xiaokun; Lv, He; Zheng, Riliang; Feng, Liqun; Huang, Yining; Yuan, Yun; Wang, Zhaoxia

doi:10.1038/jhg.2011.96

Cited by 28 publications

(14 citation statements)

References 41 publications

(51 reference statements)

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“…Particularly, the down regulation of mitochondrially encoded subunits of respiratory chain complexes testified in our study might play key roles in the age-related dysfunction of mitochondria. The complex I, or nicotine-amide adenine dinucleotide (NADH) dehydrogenase, is the largest protein complex in mitochondrial respiratory chain [20–22]. Complex I consists of more than 40 subunits, seven of which are encoded by mtDNA, named as mitochondrially encoded NADH dehydrogenase (mt-Nd), including mt-Nd1, mt-Nd2, mt-Nd3, mt-Nd4, mt-Nd4L, mt-Nd5 and mt-Nd6.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial dysfunction and endoplasmic reticulum stress involved in oocyte aging: an analysis using single-cell RNA-sequencing of mouse oocytes

Zhang

Wang

et al. 2019

J Ovarian Res

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Object To explore the mechanisms of ovarian aging, we performed overall analysis on the age-related alterations of gene expression profiles in mouse germinal vesicle (GV) stage oocytes by means of single-cell RNA-sequencing method (scRNA-seq). Methods Two age groups (5-week-old and 32-week-old) female KM mice were used as young and old models. Subsequently, GV oocytes were collected for scRNA-seq. The bioinformatics was performed to analyze and compare the differences of gene expression profile between GV oocytes of young and old mice. Results The analysis of scRNA-seq data showed that there were 624 differential expressed genes (DEGs) between two age groups of mouse GV stage oocytes. Four hundred forty-nine DEGs were up-regulated while 175 DEGs were down-regulated in the GV oocytes of the old group. KEGG pathway analysis revealed that the genes involved in mitochondrial function including oxidative phosphorylation and ATP production pathway were significantly down-regulated in GV oocytes of 32-week-old mice, especially the mitochondrial encoded NADH dehydrogenase (mt-Nd), including mt-Nd2, mt-Nd3, mt-Nd4, mt-Nd4L and mt-Nd5. Analysis of DEGs revealed that endoplasmic reticulum stress-related genes including AdipoR2, IRAK-1, RCAN1 and MsrB1 were significantly down-regulated in GV oocytes of 32-week-old mice. Also, analysis of DEGs demonstrated that anti-oxidation-related genes including Erbb3、Rcan1、Gsto2 and Msrb1 were significantly down-regulated in GV oocytes of old group. Conclusion The disorder of mitochondrial function, endoplasmic reticulum stress and the reduced antioxidant capability might be involved in the progression of oocyte aging. Especially, the down regulation of mitochondrial encoded subunits of respiratory chain complexes might play critical roles in the relevant mechanisms. Electronic supplementary material The online version of this article (10.1186/s13048-019-0529-x) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Mitochondrial dysfunction and endoplasmic reticulum stress involved in oocyte aging: an analysis using single-cell RNA-sequencing of mouse oocytes

Zhang

Wang

et al. 2019

J Ovarian Res

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“…All metabolites evaluated were decreased in FTD3 patients, heterozygous and homozygous astrocytes compared to respective controls, which supports the observed energy hypometabolism. Reduced expression of MT-ND genes could explain the observed dysfunction of mitochondrial respiratory chain with subsequent reduced ATP production [69]. In addition, we found mitochondrial uncoupling protein 2&3 (UCP2 and UCP3) genes which code for transporter proteins that create proton leaks across the inner mitochondrial membrane, to be down-regulated in FTD3 patient astrocytes.…”

Section: Hipsc-ftd3 Astrocytes Display Glucose and Acetate Hypometabomentioning

confidence: 83%

Astrocytic Reactivity Triggered by defective Mitophagy Activates NF-kB Signaling and Causes Neurotoxicity in Frontotemporal Dementia Type 3

Chandrasekaran¹,

Dittlau²,

Corsi³

et al. 2021

Preprint

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Background: Frontotemporal dementia type 3 (FTD3) caused by a point mutation in the charged multivesicular body protein 2B (CHMP2B), affects mitochondrial ultrastructure and function as well as endosomal-lysosomal fusion in neurons. However, there is a critical knowledge gap in understanding how mutations in CHMP2B affect astrocytes. Hence, we investigated the disease mechanisms in astrocytes derived from hiPSC with mutations in CHMP2B and their impact on neurons.Methods: To dissect the astrocyte-specific impact of mutant CHMP2B expression, we generated astrocytes from human induced pluripotent stem cells (hiPSCs) from FTD3 patients and their CRISPR/Cas 9 gene edited isogenic controls and produced heterozygous and homozygous CHMP2B-mutant hiPSC via CRISPR/Cas 9 knock-in gene editing. Additionally, we confirmed our findings in CHMP2B mutant mice. The hiPSC were subjected to astrocyte differentiation and the mutation dependent effects were investigated using immunocytochemistry, western blot, cytokine assays, transmission electron microscopy, RNA-sequencing and gas chromatography-mass spectrometry. Finally, neurons were exposed to conditioned media of mutant astrocytes and viability, growth and motility were measured.Results: To dissect the astrocyte-specific impact of mutant CHMP2B expression, we generated astrocytes from human induced pluripotent stem cells (hiPSCs) and confirmed our findings in CHMP2B mutant mice. Our findings include perturbed mitochondrial dynamics with impaired glycolysis, increased reactive oxygen species and elongated mitochondrial morphology, indicating increased mitochondrial fusion in FTD3 astrocytes. Furthermore, we identified a shift in astrocyte homeostasis triggering a reactive astrocyte phenotype and increased release of toxic cytokines. This cumulates in NF-kB pathway activation with increased production of CHF, LCN2 and C3, which cause neurodegeneration. The neurotoxic effect was investigated by exposing hiPSC-derived neurons to astrocyte-conditioned media, which severely reduced neurite outgrowth capacities. Rescue experiments targeting ROS could restore ROS levels back to normal levels, indicating that the impaired removal of abnormal mitochondria triggers the pathological cascade in CHMP2B mutant astrocytes culminating in the formation of neurotoxic reactive astrocytes.Conclusion :Our data provide mechanistic insights into how defective mitophagy causes impaired mitochondrial fission, leading to the adoption of reactive astrocyte properties with increased cytokine release, NFkB activation and elevated expression of neurotoxic proteins in FTD3.

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“…Including our proband, the m.10191T>C mutation has been reported in 22 patients to date (Table 3). 6,8,[11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26] There is a vast spectrum of clinical presentations and ages at onset. Most individuals had abnormal brain imaging consistent with Leigh syndrome, but diagnoses of mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes and nonspecific encephalopathy were also given.…”

Section: Discussionmentioning

confidence: 99%

Long Survival in Patients With Leigh Syndrome and the m.10191T>C Mutation in MT-ND3

et al. 2013

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We report an unusual case history of Leigh syndrome due to the m.10191T>C mutation in the complex I gene MT-ND3. This mutation has been associated with a spectrum of clinical phenotypes ranging from infant lethality to adult onset. Despite infantile onset and severe symptoms, our patient has survived to early adulthood due to a strict dietary regimen and parental care. This patient is an extreme example of the frequently prolonged course of Leigh syndrome due to this particular mutation.

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Mutations in mitochondrially encoded complex I enzyme as the second common cause in a cohort of Chinese patients with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes

Cited by 28 publications

References 41 publications

Mitochondrial dysfunction and endoplasmic reticulum stress involved in oocyte aging: an analysis using single-cell RNA-sequencing of mouse oocytes

Mitochondrial dysfunction and endoplasmic reticulum stress involved in oocyte aging: an analysis using single-cell RNA-sequencing of mouse oocytes

Astrocytic Reactivity Triggered by defective Mitophagy Activates NF-kB Signaling and Causes Neurotoxicity in Frontotemporal Dementia Type 3

Long Survival in Patients With Leigh Syndrome and the m.10191T>C Mutation in MT-ND3

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