Mitochondrial DNA Mutation Load

DiMauro, Salvatore

doi:10.1001/jamaneurol.2013.4401

Cited by 4 publications

(4 citation statements)

References 14 publications

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“…Large mitochondrial DNA (mtDNA) deletions were first discovered in muscle of patients with mitochondrial myopathies (MM), Kearns-Sayre syndrome (KSS) (OMI M530000), Pearson syndrome (OMIM557000), and progressive external ophthalmoplegia (PEO; OMIM555000) [27][28][29][30]. MtDNA deletion syndromes have been also reported in patients with various clinical manifestations, including Addison disease, atypical Pearson presentation, cyclic vomiting, severe renal tubulopathy, hepatic dysfunction, dysarthria, organic acidopathy, hypoparathyroidism, and hypocalcemia [31].…”

Section: Discussionmentioning

confidence: 99%

Large‐scale mitochondrial DNA deletion underlying familial multiple system atrophy of the cerebellar subtype

Alsemari

Alhindi

2015

Clinical Case Reports

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Section: Discussionmentioning

confidence: 99%

Large‐scale mitochondrial DNA deletion underlying familial multiple system atrophy of the cerebellar subtype

Alsemari

Alhindi

2015

Clinical Case Reports

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“…Classical histochemistry techniques allow visualizing succinate dehydrogenase (SDH) and cytochrome c oxidase (COX) activity. Indeed, the most informative histochemical impairment of mitochondria in skeletal muscle is ragged red fibers (RRF), observed on frozen sections traditionally with the modified Gomori trichrome method [24]. Since the accumulation of material other than mitochondria sometimes simulates a RRF appearance, the identification of deposits suspected of being mitochondrial proliferation should be confirmed by histochemical staining of oxidative enzymes as SDH and COX.…”

Section: Biochemical Analysis Of Mitochondrial Respiration: a Potentimentioning

confidence: 99%

Pathogenic Implications of Human Mitochondrial Aminoacyl-tRNA Synthetases

Schwenzer

Zoll

Florentz

et al. 2013

Topics in Current Chemistry

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Mitochondria are considered as the powerhouse of eukaryotic cells. They host several central metabolic processes fueling the oxidative phosphorylation pathway (OXPHOS) that produces ATP from its precursors ADP and inorganic phosphate Pi (PPi). The respiratory chain complexes responsible for the OXPHOS pathway are formed from complementary sets of protein subunits encoded by the nuclear genome and the mitochondrial genome, respectively. The expression of the mitochondrial genome requires a specific and fully active translation machinery from which aminoacyl-tRNA synthetases (aaRSs) are key actors. Whilst the macromolecules involved in mammalian mitochondrial translation have been under investigation for many years, there has been an explosion of interest in human mitochondrial aaRSs (mt-aaRSs) since the discovery of a large (and growing) number of mutations in these genes that are linked to a variety of neurodegenerative disorders. Herein we will review the present knowledge on mt-aaRSs in terms of their biogenesis, their connection to mitochondrial respiration, i.e., the respiratory chain (RC) complexes, and to the mitochondrial translation machinery. The pathology-related mutations detected so far are described, with special attention given to their impact on mt-aaRSs biogenesis, functioning, and/or subsequent activities. The collected data to date shed light on the diverse routes that are linking primary molecular possible impact of a mutation to its phenotypic expression. It is envisioned that a variety of mechanisms, inside and outside the translation machinery, would play a role on the heterogeneous manifestations of mitochondrial disorders.

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“…Phenotypic variability arises -at least in part -as a result of heteroplasmy, coupled with varying proportions of mutant and WT mtDNA in different tissues. The severity of the syndrome tends to be determined by the ratio of mutant to WT mtDNA (6,7,8). Very few studies have analyzed the mutational load and diverse clinical manifestation in patients with MELAS syndrome.…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial diabetes and mitochondrial DNA mutation load in MELAS syndrome

Chae

Kim

et al. 2020

European Journal of Endocrinology

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Objective: Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a very rare condition; it encompasses a diverse group of disorders including diabetes. Phenotypic variability can be attributed to heteroplasmy along with varying proportions of mutant and WT mitochondrial DNA (mtDNA). To examine the clinical relationship between mitochondrial diabetes and mutational load, we analyzed the mtDNA of children and young adolescents with MELAS syndrome using next generation sequencing (NGS). Design and methods: Of 57 subjects with suspected MELAS syndrome, 32 children and young adolescents were diagnosed as MELAS syndrome with mtDNA A-to-G transition at nucleotide 3243. Mutation load studies and NGS were performed for 25 subjects. Results: The mean mutation load was 60.4 ± 18.4% (range: 22.5‒100). Of the 25 subjects with NGS results, 15 (60%) were diagnosed with DM and 2 (8%) were diagnosed with impaired glucose tolerance (IGT). The mutational load of subjects inversely correlated with first symptom onset, age at diagnosis of MELAS syndrome, and DM (P < 0.001). However, mutational load did not correlate with the clinical severity or progression of DM/IGT. There was no significant difference in insulin resistance or sensitivity indices between the low- and high-mutation load groups. During the 3.7 years of follow-up, insulin resistance indices were not significantly different between baseline and follow-up. Conclusions: We can infer that the mutation load in the MELAS syndrome is significantly associated with the onset of symptoms and associated diseases, including mitochondrial diabetes. However, it may not influence disease progression.

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Mitochondrial DNA Mutation Load

Cited by 4 publications

References 14 publications

Large‐scale mitochondrial DNA deletion underlying familial multiple system atrophy of the cerebellar subtype

Large‐scale mitochondrial DNA deletion underlying familial multiple system atrophy of the cerebellar subtype

Pathogenic Implications of Human Mitochondrial Aminoacyl-tRNA Synthetases

Mitochondrial diabetes and mitochondrial DNA mutation load in MELAS syndrome

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