Immunohistochemical analysis of the oxidative phosphorylation complexes in skeletal muscle from patients with mitochondrial DNA encoded tRNA gene defects

Paepe, Boél De; Smet, Joél; Lammens, Martin; Seneca, Sara; Martin, Jean‐Jacques; Bleecker, Jan De; Meırleır, Linda De; Lissens, Willy; Coster, Rudy Van

doi:10.1136/jcp.2008.061267

Cited by 15 publications

(13 citation statements)

References 25 publications

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“…COX activity in muscle fibers is decreased or absent in most patients with MERRF ( Figure 3) 4,27,45,54,55 . As mentioned previously, the presence of COX-fibers in patients with MERRF is greater than that found in other mitochondrial diseases, such as MELAS, demonstrating that different mutations of mtDNA may influence the histological findings in different mitochondrial disorders 40,45,46,47,48,52 . The presence of vessels in the muscle biopsy, usually arterioles, with a strong reaction to SDH (SDH+) can be found more often in patients with MELAS or MERRF than in PEO patients 40,52,56,57 .…”

Section: What Are the Histological Features?mentioning

confidence: 85%

“…Complexes I and IV seem to be more involved in the respiratory chain in patients with MERRF, and they are usually associated with changes in other respiratory chain complexes, whereas complex II seems to be the least affected 8,23,27,34,42,43,44 . The number of muscle fibers with deficient activity of COX observed upon muscle biopsy suggests that respiratory chain complex IV could be one of the complexes that are most affected in MERRF patients 45,46,47,48,49,50,51,52,53,54,55,56,57 . This reasoning can also be supported by the fact that patients with MERRF who have the A8344G point mutation also exhibit a high frequency of muscle fibers (RRF and no-RRF) with deficient COX activity upon muscle biopsy 26, 45,48 .…”

Section: What Are the Laboratory And Biochemical Features?mentioning

confidence: 99%

“…A quantitative analysis shows that 80 to 90% of muscle fibers have a higher amount of mtDNA (normal and mutant), and the proportion of mutant mtDNA is extremely high in RRF when compared with fibers that do not form RRF 18,27,53 . The morphological changes observed in muscle biopsies that can help distinguish MERRF from other mitochondrial diseases are as follows: (1) a large proportion of muscle fibers (RRF and no-RRF) that have deficient activity of cytochrome c oxidase (COX), and (2) the presence of COX deficient vessels with a strong reaction for SDH 45,46,47 . COX activity in muscle fibers is decreased or absent in most patients with MERRF ( Figure 3) 4,27,45,54,55 .…”

Section: What Are the Histological Features?mentioning

confidence: 99%

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When should MERRF (myoclonus epilepsy associated with ragged-red fibers) be the diagnosis?

Lorenzoni

Scola

Kay

et al. 2014

Arq. Neuro-Psiquiatr.

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Myoclonic epilepsy associated with ragged red fibers (MERRF) is a rare mitochondrial disorder. Diagnostic criteria for MERRF include typical manifestations of the disease: myoclonus, generalized epilepsy, cerebellar ataxia and ragged red fibers (RRF) on muscle biopsy. Clinical features of MERRF are not necessarily uniform in the early stages of the disease, and correlations between clinical manifestations and physiopathology have not been fully elucidated. It is estimated that point mutations in the tRNA Lys gene of the DNAmt, mainly A8344G, are responsible for almost 90% of MERRF cases. Morphological changes seen upon muscle biopsy in MERRF include a substantive proportion of RRF, muscle fibers showing a deficient activity of cytochrome c oxidase (COX) and the presence of vessels with a strong reaction for succinate dehydrogenase and COX deficiency. In this review, we discuss mainly clinical and laboratory manifestations, brain images, electrophysiological patterns, histology and molecular findings as well as some differential diagnoses and treatments.Keywords: MERRF, mitochondrial, epilepsy, myoclonus, myopathy. RESUMOEpilepsia mioclônica associada com fibras vermelhas rasgadas (MERRF) é uma rara doença mitocondrial. O critério diagnóstico para MERRF inclui as manifestações típicas da doença: mioclonia, epilepsia generalizada, ataxia cerebelar e fibras vermelhas rasgadas (RRF) na biópsia de músculo. Na fase inicial da doença, as manifestações clínicas podem não ser uniformes, e correlação entre as manifestações clínicas e fisiopatologia não estão completamente elucidadas. Estima-se que as mutações de ponto no gene tRNA Lys do DNAmt, principalmente a A8344G, sejam responsáveis por quase 90% dos casos de MERRF. As alterações morfológicas na biópsia muscular incluem uma grande proporção de RRF, fibras musculares com deficiência de atividade da citocromo c oxidase (COX) e presença de vasos com forte reação para succinato desidrogenase e deficiência da COX. Nesta revisão, são discutidas as principais manifestações clínicas e laboratoriais, imagens cerebrais, padrões eletrofisiológicos, histológicos e alterações moleculares, bem como, alguns dos diagnósticos diferenciais e tratamentos.

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Section: What Are the Histological Features?mentioning

confidence: 85%

Section: What Are the Laboratory And Biochemical Features?mentioning

confidence: 99%

Section: What Are the Histological Features?mentioning

confidence: 99%

See 1 more Smart Citation

When should MERRF (myoclonus epilepsy associated with ragged-red fibers) be the diagnosis?

Lorenzoni

Scola

Kay

et al. 2014

Arq. Neuro-Psiquiatr.

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“…Cells were air-dried for 3 minutes and then incubated at 37°C with freshly prepared staining buffer. Histochemical staining was performed as previously described (De Paepe et al, 2009) with some modifications. For COX, the staining buffer consisted of 10% sucrose, 100 μM of fully reduced bovine cytochrome C, 8 units catalase, 1 mg/ml 3,3′-diaminobenzidine (DAB) and 0.25% DMSO in 20 mM sodium phosphate buffer (pH 7).…”

Section: Methodsmentioning

confidence: 99%

Screen for abnormal mitochondrial phenotypes in mouse ES cells identifies model for Succinyl-CoA Ligase deficiency and mtDNA depletion

Donti

Stromberger

et al. 2013

Disease Models &Amp; Mechanisms

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Mutations in subunits of succinyl-CoA synthetase/ligase (SCS), a component of the citric acid cycle, are associated with mitochondrial encephalomyopathy, elevation of methylmalonic acid (MMA), and mitochondrial DNA (mtDNA) depletion. A FACS-based retroviral-mediated gene trap mutagenesis screen in mouse embryonic stem (ES) cells for abnormal mitochondrial phenotypes identified a gene trap allele of Sucla2 (Sucla2SAβgeo), which was used to generate transgenic mice. Sucla2 encodes the ADP-specific β-subunit isoform of SCS. Sucla2SAβgeo homozygotes exhibited recessive lethality, with most mutants dying late in gestation (e18.5). Mutant placenta and embryonic (e17.5) brain, heart and muscle showed varying degrees of mtDNA depletion (20–60%). However, there was no mtDNA depletion in mutant liver, where the gene is not normally expressed. Elevated levels of MMA were observed in embryonic brain. SCS-deficient mouse embryonic fibroblasts (MEFs) demonstrated a 50% reduction in mtDNA content compared with wild-type MEFs. The mtDNA depletion resulted in reduced steady state levels of mtDNA encoded proteins and multiple respiratory chain deficiencies. mtDNA content could be restored by reintroduction of Sucla2. This mouse model of SCS deficiency and mtDNA depletion promises to provide insights into the pathogenesis of mitochondrial diseases with mtDNA depletion and into the biology of mtDNA maintenance. In addition, this report demonstrates the power of a genetic screen that combines gene trap mutagenesis and FACS analysis in mouse ES cells to identify mitochondrial phenotypes and to develop animal models of mitochondrial dysfunction.

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“…Convenient methods have been developed for human tissues [172] and cultured skin fibroblasts [173,174]. In addition, diagnostic and prognostic mitochondrial markers have been developed for cancer.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial Markers for Cancer: Relevance to Diagnosis, Therapy, and Prognosis and General Understanding of Malignant Disease Mechanisms

Paepe

2012

ISRN Pathology

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Cancer cells display changes that aid them to escape from cell death, sustain their proliferative powers, and shift their metabolism toward glycolytic energy production. Mitochondria are key organelles in many metabolic and biosynthetic pathways, and the adaptation of mitochondrial function has been recognized as crucial to the changes that occur in cancer cells. This paper zooms in on the pathologic evaluation of mitochondrial markers for diagnosing and staging of human cancer and determining the patients’ prognoses.

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Immunohistochemical analysis of the oxidative phosphorylation complexes in skeletal muscle from patients with mitochondrial DNA encoded tRNA gene defects

Cited by 15 publications

References 25 publications

When should MERRF (myoclonus epilepsy associated with ragged-red fibers) be the diagnosis?

When should MERRF (myoclonus epilepsy associated with ragged-red fibers) be the diagnosis?

Screen for abnormal mitochondrial phenotypes in mouse ES cells identifies model for Succinyl-CoA Ligase deficiency and mtDNA depletion

Mitochondrial Markers for Cancer: Relevance to Diagnosis, Therapy, and Prognosis and General Understanding of Malignant Disease Mechanisms

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