Revelation of a New Mitochondrial DNA Mutation (G12147A) in a MELAS/MERFF Phenotype

Melone, Mariarosa Anna Beatrice; Tessa, Alessandra; Petrini, Stefania; Lus, Giacomo; Sampaolo, Simone; Fede, Giuseppe Di; Santorelli, Filippo M.; Cotrufo, Roberto

doi:10.1001/archneur.61.2.269

Cited by 66 publications

(34 citation statements)

References 14 publications

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“…It has been reported that synapsis of homozygous chromosomes in the mammalian spermatogenic meiotic process begins at the zygotene stage through chromosome movement and attachment [6,24] and that several factors for synaptonemal complexes of homozygous chromosomes, such as RAD51, DMC1, and cohesin, contain functional ATP binding domains [1,30,43]. Actually, abnormal and incomplete attachment of homozygous chromosomes occurred only in mito-mice∆ with a high load of ∆mtDNA.…”

Section: Male Infertility In Mito-mice∆mentioning

confidence: 99%

“…Dementia and ataxia are sometime found in patients with traditional mitochondrial diseases caused by accumulation of mutated mtDNAs, such as MELAS (mitochondrial encephalopathy, lactic acidosis, and strokelike episodes), MERRF (myoclonic epilepsy and ragged red fibers), KSS (Kearns-Sayre Syndrome), CPeO (chronic progressive external ophthalmoplegia), and NARP (neurogenic muscle weakness, ataxia, and retinitis pigmentosa) [1,6,13,24,30,43], and the same mutated mtDNAs have been identified in patients with dementia, ataxia, and Alzheimer's disease [31,42]. Moreover, there appears to be a relationship between mtDNA polymorphisms and cognitive function in humans [38].…”

Section: Abnormalities Of Spatial Remote Memory In Mito-mice∆mentioning

confidence: 99%

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Transmitochondrial Mice as Models for Mitochondrial DNA-Based Diseases

Nakada

Hayashi

2011

Exp. Anim.

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Mitochondrial genome (mtDNA) mutations and the resultant mitochondrial respiratory abnormalities are associated with a wide variety of disorders, such as mitochondrial diseases, neurodegenerative diseases, diabetes, and cancer, as well as aging. Generation of model animals carrying mutant mtDNAs is important for understanding the pathophysiological mechanisms of the mtDNA-based diseases. We have succeeded in generating three kinds of mice with pathogenic mutant mtDNAs, named "mito-mice," by the introduction of mitochondria carrying pathogenic mutant mtDNAs into mouse zygotes and mouse embryonic stem (ES) cells. In the case of mito-mice possessing the heteroplasmic state of wild-type mtDNA and pathogenic mtDNA with a large-scale deletion (∆mtDNA, mito-mice∆), a high load of ∆mtDNA induced mitochondrial respiration defects in various tissues, resulting in mitochondrial disease phenotypes, such as low body weight, lactic acidosis, ischemia, myopathy, heart block, deafness, male infertility, long-term memory defects, and renal failure. In this review, we summarize generation and clinical phenotypes of three types of mito-mice and we introduce several treatment trials for mitochondrial diseases using mito-mice∆.

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Section: Male Infertility In Mito-mice∆mentioning

confidence: 99%

Section: Abnormalities Of Spatial Remote Memory In Mito-mice∆mentioning

confidence: 99%

Transmitochondrial Mice as Models for Mitochondrial DNA-Based Diseases

Nakada

Hayashi

2011

Exp. Anim.

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“…often caused by numerous point mutations (G611A, A3243G, A8344G, G8361A, G12147A) in mtDNA, which affect genes encoding different mitochondrial tRNAs (Mancuso et al, 2004;Mongini et al, 2002;Shoffner et al, 1990;Rossmanith et al, 2003;Melone et al, 2004), is also to some extent associated with lipid-storage disorders and TG accumulation in muscles (MunozMalaga et al, 2000;Naumann et al, 1997). It has also been shown that most of multiple symmetrical lipomatosis (MSL) patients also display mitochondrial dysfunction Berkovic et al, 1991), lipomas that contain atypical multivacuolar white adipocytes (Zancanaro et al, 1990) as well as ragged red fibers and TG accumulation in muscles (Klopstock et al, 1997;Munoz-Malaga et al, 2000).…”

Section: Journal Of Cell Science 119 (7)mentioning

confidence: 99%

CREB activation induced by mitochondrial dysfunction triggers triglyceride accumulation in 3T3-L1 preadipocytes

Vankoningsloo

Pauw

Houbion

et al. 2006

Journal of Cell Science

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Several mitochondrial pathologies are characterized by lipid redistribution and microvesicular cell phenotypes resulting from triglyceride accumulation in lipid-metabolizing tissues. However, the molecular mechanisms underlying abnormal fat distribution induced by mitochondrial dysfunction remain poorly understood. In this study, we show that inhibition of respiratory complex III by antimycin A as well as inhibition of mitochondrial protein synthesis trigger the accumulation of triglyceride vesicles in 3T3-L1 fibroblasts. We also show that treatment with antimycin A triggers CREB activation in these cells. To better delineate how mitochondrial dysfunction induces triglyceride accumulation in preadipocytes, we developed a low-density DNA microarray containing 89 probes, which allows gene expression analysis for major effectors and/or markers of adipogenesis. We thus determined gene expression profiles in 3T3-L1 cells incubated with antimycin A and compared the patterns obtained with differentially expressed genes during the course of in vitro adipogenesis induced by a standard pro-adipogenic cocktail. After an 8-day treatment, a set of 39 genes was found to be differentially expressed in cells treated with antimycin A, among them CCAAT/enhancer-binding protein α (C/EBPα), C/EBP homologous protein-10 (CHOP-10), mitochondrial glycerol-3-phosphate dehydrogenase (GPDmit), and stearoyl-CoA desaturase 1 (SCD1). We also demonstrate that overexpression of two dominant negative mutants of the cAMP-response element-binding protein CREB (K-CREB and M1-CREB) and siRNA transfection, which disrupt the factor activity and expression, respectively, inhibit antimycin-A-induced triglyceride accumulation. Furthermore, CREB knockdown with siRNA also downregulates the expression of several genes that contain cAMP-response element (CRE) sites in their promoter, among them one that is potentially involved in synthesis of triglycerides such as SCD1. These results highlight a new role for CREB in the control of triglyceride metabolism during the adaptative response of preadipocytes to mitochondrial dysfunction.

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“…Quantification of mutant mtDNA used a mispairing PCR method and employed the endonuclease RsaI. Single muscle fibers were selected, isolated, and analyzed by PCR using a modification of the laser capture microdissection (LCM-PCR) technique which allows the selective sampling of tissue from histological sections [13,14]. The aforementioned PCR-RFLP strategy allowed us to quantify levels of mutant mtDNAs in single myocytes.…”

Section: Methodsmentioning

confidence: 99%

Identification of a new mtDNA mutation (14724G>A) associated with mitochondrial leukoencephalopathy

Pereira

Nogueira

Barbot

et al. 2007

Biochemical and Biophysical Research Communications

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We report a novel 14724G>A mutation in the mitochondrial tRNA glutamic acid gene in a 4-year-old boy with myopathy and leukoencephalopathy. A muscle biopsy showed cytochrome c oxidase-negative ragged-red fibers and biochemical analysis of the respiratory chain enzymes in muscle homogenate revealed partial complex I and complex IV deficiencies. The mutation, which affects the dihydrouridine arm at a conserved site, was nearly homoplasmic in muscle and heteroplasmic in blood DNA of the proband, but it was absent in peripheral leukocytes from the asymptomatic mother, sister, and two maternal aunts, suggesting that it arose de novo. This report proposes to look for variants in the mitochondrial genome when dealing with otherwise undetermined leukodystrophies of childhood.

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Revelation of a New Mitochondrial DNA Mutation (G12147A) in a MELAS/MERFF Phenotype

Abstract: Our data propose that the G12147A change, the first mutation in the transfer RNA(His) gene associated with an overlapped MELAS/MERFF phenotype, is the cause of the encephalomyopathy in this patient interfering with the overall mitochondrial protein synthesis.

Cited by 66 publications

References 14 publications

Transmitochondrial Mice as Models for Mitochondrial DNA-Based Diseases

Transmitochondrial Mice as Models for Mitochondrial DNA-Based Diseases

CREB activation induced by mitochondrial dysfunction triggers triglyceride accumulation in 3T3-L1 preadipocytes

Identification of a new mtDNA mutation (14724G>A) associated with mitochondrial leukoencephalopathy

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