Generation of two isogenic human induced pluripotent stem cell lines from a 15 year-old female patient with MERRF syndrome and A8344G mutation of mitochondrial DNA

Chou, Shih Jie; Ko, Yu Ling; Yang, Yi; Yarmishyn, Aliaksandr A.; Wu, Yu; Chen, Chien Tsun; Wei, Yau‐Huei; Chiou, Shih Hwa

doi:10.1016/j.scr.2018.05.011

Cited by 12 publications

(6 citation statements)

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“…The 6 lines of human iPSCs used in this study were generated from the skin fibroblasts established from 3 patients harboring the MERRF syndrome-specific m.8344A > G mutation. Among them, two patients are the members of a Taiwanese MERRF family, a 15-year-old girl (M1-iPSCs) and her 13-year-old sister (M2-iPSCs), and the third patient is a 25-year-old female (M3-iPSCs) as described previously [ 12 , 14 , 16 ]. M1 patient had poor learning ability in childhood and developed myoclonic epilepsy at 12 years of age, and exhibited severe clinical symptoms, including unsteady gait with tremor, intermittent myoclonus and polyneuropathy [ 17 ].…”

Section: Methodsmentioning

confidence: 99%

Mitochondrial impairment and synaptic dysfunction are associated with neurological defects in iPSCs-derived cortical neurons of MERRF patients

Wu,

Tay,

Yang

et al. 2023

J Biomed Sci

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Background Myoclonic epilepsy with ragged-red fibers (MERRF) syndrome is a rare inherited mitochondrial disease mainly caused by the m.8344A > G mutation in mitochondrial tRNALys gene, and usually manifested as complex neurological disorders and muscle weakness. Currently, the pathogenic mechanism of this disease has not yet been resolved, and there is no effective therapy for MERRF syndrome. In this study, MERRF patients-derived iPSCs were used to model patient-specific neurons for investigation of the pathogenic mechanism of neurological disorders in mitochondrial disease. Methods MERRF patient-derived iPSCs were differentiated into excitatory glutamatergic neurons to unravel the effects of the m.8344A > G mutation on mitochondrial bioenergetic function, neural-lineage differentiation and neuronal function. By the well-established differentiation protocol and electrophysiological activity assay platform, we examined the pathophysiological behaviors in cortical neurons of MERRF patients. Results We have successfully established the iPSCs-derived neural progenitor cells and cortical-like neurons of patients with MERRF syndrome that retained the heteroplasmy of the m.8344A > G mutation from the patients’ skin fibroblasts and exhibited the phenotype of the mitochondrial disease. MERRF neural cells harboring the m.8344A > G mutation exhibited impaired mitochondrial bioenergetic function, elevated ROS levels and imbalanced expression of antioxidant enzymes. Our findings indicate that neural immaturity and synaptic protein loss led to the impairment of neuronal activity and plasticity in MERRF neurons harboring the m.8344A > G mutation. By electrophysiological recordings, we monitored the in vivo neuronal behaviors of MERRF neurons and found that neurons harboring a high level of the m.8344A > G mutation exhibited impairment of the spontaneous and evoked potential-stimulated neuronal activities. Conclusions We demonstrated for the first time the link of mitochondrial impairment and synaptic dysfunction to neurological defects through impeding synaptic plasticity in excitatory neurons derived from iPSCs of MERRF patients harboring the m.8344A > G mutation. This study has provided new insight into the pathogenic mechanism of the tRNALys gene mutation of mtDNA, which is useful for the development of a patient-specific iPSCs platform for disease modeling and screening of new drugs to treat patients with MERRF syndrome.

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Section: Methodsmentioning

confidence: 99%

Mitochondrial impairment and synaptic dysfunction are associated with neurological defects in iPSCs-derived cortical neurons of MERRF patients

Wu,

Tay,

Yang

et al. 2023

J Biomed Sci

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“…Known mutations affecting mitochondrial protein synthesis include transitions m.8344A > G in the tRNA-Lys gene and m.3243A > G in the tRNA-Leu gene. Both are associated with MERRF and MELAS syndromes (Chou et al, 2018). Patients with MERRF syndrome typically present with cardiomyopathy, dysrhythmia and neuropathy.…”

Section: Mtdna Mutations Associated With Neurodegenerative and Cardiovascular Diseasesmentioning

confidence: 99%

The Role of Mitochondrial Dysfunction in Vascular Disease, Tumorigenesis, and Diabetes

Жунина

Yabbarov

Grechko

et al. 2021

Front. Mol. Biosci.

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Mitochondrial dysfunction is known to be associated with a wide range of human pathologies, such as cancer, metabolic, and cardiovascular diseases. One of the possible ways of mitochondrial involvement in the cellular damage is excessive production of reactive oxygen and nitrogen species (ROS and RNS) that cannot be effectively neutralized by existing antioxidant systems. In mitochondria, ROS and RNS can contribute to protein and mitochondrial DNA (mtDNA) damage causing failure of enzymatic chains and mutations that can impair mitochondrial function. These processes further lead to abnormal cell signaling, premature cell senescence, initiation of inflammation, and apoptosis. Recent studies have identified numerous mtDNA mutations associated with different human pathologies. Some of them result in imbalanced oxidative phosphorylation, while others affect mitochondrial protein synthesis. In this review, we discuss the role of mtDNA mutations in cancer, diabetes, cardiovascular diseases, and atherosclerosis. We provide a list of currently described mtDNA mutations associated with each pathology and discuss the possible future perspective of the research.

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“…Since the epochal discovery of induced pluripotent stem cells by the Yamanaka group in 2006 ( 28 ), many researchers generated hiPSC by reprogramming differentiated cells obtained from mitochondrial disease patients [MELAS syndrome ( 29 ), MERRF syndrome ( 30 ), Pearson syndrome ( 31 ); reviewed by Liang ( 32 )]. Unexpectedly, even if LHON is the most-frequent mitochondrial disease, to date only a few groups, including ours ( 33 ), had generated LHON hiPSCs by reprogramming fibroblasts or peripheral blood mononuclear cells (PBMCs) derived from patients ( 34 – 38 ).…”

Section: Reprogramming Fibroblasts or Peripheral Blood Mononuclear Cells Pbmcs From Lhon Patientsmentioning

confidence: 99%

Exploiting hiPSCs in Leber's Hereditary Optic Neuropathy (LHON): Present Achievements and Future Perspectives

et al. 2021

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More than 30 years after discovering Leber's hereditary optic neuropathy (LHON) as the first maternally inherited disease associated with homoplasmic mtDNA mutations, we still struggle to achieve effective therapies. LHON is characterized by selective degeneration of retinal ganglion cells (RGCs) and is the most frequent mitochondrial disease, which leads young people to blindness, in particular males. Despite that causative mutations are present in all tissues, only a specific cell type is affected. Our deep understanding of the pathogenic mechanisms in LHON is hampered by the lack of appropriate models since investigations have been traditionally performed in non-neuronal cells. Effective in-vitro models of LHON are now emerging, casting promise to speed our understanding of pathophysiology and test therapeutic strategies to accelerate translation into clinic. We here review the potentials of these new models and their impact on the future of LHON patients.

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Generation of two isogenic human induced pluripotent stem cell lines from a 15 year-old female patient with MERRF syndrome and A8344G mutation of mitochondrial DNA

Cited by 12 publications

References 5 publications

Mitochondrial impairment and synaptic dysfunction are associated with neurological defects in iPSCs-derived cortical neurons of MERRF patients

Mitochondrial impairment and synaptic dysfunction are associated with neurological defects in iPSCs-derived cortical neurons of MERRF patients

The Role of Mitochondrial Dysfunction in Vascular Disease, Tumorigenesis, and Diabetes

Exploiting hiPSCs in Leber's Hereditary Optic Neuropathy (LHON): Present Achievements and Future Perspectives

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Generation of two isogenic human induced pluripotent stem cell lines from a 15 year-old female patient with MERRF syndrome and A8344G mutation of mitochondrial DNA

Cited by 12 publications

References 5 publications

Mitochondrial impairment and synaptic dysfunction are associated with neurological defects in iPSCs-derived cortical neurons of MERRF patients

Mitochondrial impairment and synaptic dysfunction are associated with neurological defects in iPSCs-derived cortical neurons of MERRF patients

The Role of Mitochondrial Dysfunction in Vascular Disease, Tumorigenesis, and Diabetes

Exploiting hiPSCs in Leber's Hereditary Optic Neuropathy (LHON): Present Achievements and Future Perspectives

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Generation of two isogenic human induced pluripotent stem cell lines from a 15 year-old female patient with MERRF syndrome and A8344G mutation of mitochondrial DNA