Ultrastructural Changes of Mitochondria in the Cultivated Skin Fibroblasts of Patients with Point Mutations in Mitochondrial DNA

Brantova, Olga; Tesařová, Markéta; Hansı́ková, Hana; Elleder, M; Zeman, Jiřı́; Sladkova, Jana

doi:10.1080/01913120600820112

Cited by 25 publications

(14 citation statements)

References 21 publications

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“…9). In contrast to mitochondria of father’s cells, which are filamentous as commonly seen in cultured fibroblasts, 20 mitochondria of R cells appear to be shorter and distorted. Another noticeable feature of R cells was the presence of large vesicles not seen in F cells (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 68%

Deleterious mutations in ALDH1L2 suggest a novel cause for neuro-ichthyotic syndrome

et al. 2019

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Neuro-ichthyotic syndromes are a group of rare genetic diseases mainly associated with perturbations in lipid metabolism, intracellular vesicle trafficking, or glycoprotein synthesis. Here, we report a patient with a neuro-ichthyotic syndrome associated with deleterious mutations in the ALDH1L2 (aldehyde dehydrogenase 1 family member L2) gene encoding for mitochondrial 10-formyltetrahydrofolate dehydrogenase. Using fibroblast culture established from the ALDH1L2-deficient patient, we demonstrated that the enzyme loss impaired mitochondrial function affecting both mitochondrial morphology and the pool of metabolites relevant to β-oxidation of fatty acids. Cells lacking the enzyme had distorted mitochondria, accumulated acylcarnitine derivatives and Krebs cycle intermediates, and had lower ATP and increased ADP/AMP indicative of a low energy index. Re-expression of functional ALDH1L2 enzyme in deficient cells restored the mitochondrial morphology and the metabolic profile of fibroblasts from healthy individuals. Our study underscores the role of ALDH1L2 in the maintenance of mitochondrial integrity and energy balance of the cell, and suggests the loss of the enzyme as the cause of neuro-cutaneous disease.

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Section: Resultsmentioning

confidence: 68%

Deleterious mutations in ALDH1L2 suggest a novel cause for neuro-ichthyotic syndrome

et al. 2019

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“…The proportions of wild-type to mutant mtDNA were measured using a PhosphorImager and ImageQuant software (Molecular Dynamics). The levels of heteroplasmy of the 3243A>G and 8344A>G mutations were determined as described elsewhere [16].…”

Section: Mtdna Analysismentioning

confidence: 99%

The impact of mitochondrial tRNA mutations on the amount of ATP synthase differs in the brain compared to other tissues

Fornůsková

Brantova

Tesařová

et al. 2008

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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The impact of point mutations in mitochondrial tRNA genes on the amount and stability of respiratory chain complexes and ATP synthase (OXPHOS) has been broadly characterized in cultured skin fibroblasts, skeletal muscle samples, and mitochondrial cybrids. However, less is known about how these mutations affect other tissues, especially the brain. We have compared OXPHOS protein deficiency patterns in skeletal muscle mitochondria of patients with Leigh (8363G>A), MERRF (8344A>G), and MELAS (3243A>G) syndromes. Both mutations that affect mt-tRNA(Lys) (8363G>A, 8344A>G) resulted in severe combined deficiency of complexes I and IV, compared to an isolated severe defect of complex I in the 3243A>G sample (mt-tRNA(LeuUUR). Furthermore, we compared obtained patterns with those found in the heart, frontal cortex, and liver of 8363G>A and 3243A>G patients. In the frontal cortex mitochondria of both patients, the patterns of OXPHOS deficiencies differed substantially from those observed in other tissues, and this difference was particularly striking for ATP synthase. Surprisingly, in the frontal cortex of the 3243A>G patient, whose ATP synthase level was below the detection limit, the assembly of complex IV, as inferred from 2D-PAGE immunoblotting, appeared to be hindered by some factor other than the availability of mtDNA-encoded subunits.

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“…Bernier et al [25] demonstrated ultrastructural cardiac abnormalities in only 3% of their patients studied. Fibroblasts can sometimes demonstrate ultrastructural mitochondrial abnormalities, especially in patients with mitochondrial DNA defects [46]. Patients with significant central nervous system involvement may receive a brain biopsy, but brain pathology is also nonspecific, demonstrating focal necrosis, a loss of cortical neurons, reactive astrogliosis, astrocytic inclusions, demyelination, spongiosis, endothelial proliferation, or capillary hyperplasia [17].…”

Section: Pathology Of Other Tissuesmentioning

confidence: 99%

Presentation and Diagnosis of Mitochondrial Disorders in Children

Koenig

2008

Pediatric Neurology

141

109

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The first disorder of mitochondrial function was described by Luft in 1959. Over the ensuing decades, multiple cases of mitochondrial dysfunction were reported, and the term "mitochondrial disorder" arose to describe any defect in the mitochondrial electron transport chain. The sequence of the mitochondrial genome was elucidated in 1981 by Anderson et al., and during the next 20 years, >200 pathogenic point mutations, deletions, insertions, and rearrangements were described. Most of the original cases were adults, and the diagnosis of a mitochondrial disorder in an adult patient became relatively straightforward. Adults present with well-defined "mitochondrial syndromes" and generally carry mitochondrial DNA mutations that are easily identified. Children with mitochondrial disorders are much harder to define. Children are more likely to have a nuclear DNA mutation, whereas the "classic" syndromic findings tend to be absent. This review describes both the varying presentations of mitochondrial disorders and the common laboratory, imaging, and pathologic findings related to children.

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Ultrastructural Changes of Mitochondria in the Cultivated Skin Fibroblasts of Patients with Point Mutations in Mitochondrial DNA

Cited by 25 publications

References 21 publications

Deleterious mutations in ALDH1L2 suggest a novel cause for neuro-ichthyotic syndrome

Deleterious mutations in ALDH1L2 suggest a novel cause for neuro-ichthyotic syndrome

The impact of mitochondrial tRNA mutations on the amount of ATP synthase differs in the brain compared to other tissues

Presentation and Diagnosis of Mitochondrial Disorders in Children

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