Deletions of mitochondrial DNA in Kearns‐Sayre syndrome

Zeviani, Massimo; Moraes, Carlos T.; DiMauro, Salvatore; Nakase, Hirofumi; Bonilla, Eduardo; Schon, Eric A.; Rowland, Lewis P.

doi:10.1212/wnl.38.9.1339

Cited by 468 publications

(109 citation statements)

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“…Southern blot technique allowed analysis of the size and amount of mitochondrial DNA 12. In some cases, mitochondrial DNA was also studied by restriction analysis or direct sequencing, or both 12…”

Section: Methodsmentioning

confidence: 99%

In vivo functional investigations of lactic acid in patients with respiratory chain disorders

Touati

Rigal

Lombès

et al. 1997

Archives of Disease in Childhood

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Objective-To assess the prevalence of in vivo detectable abnormalities of lactate metabolism in mitochondrial disorders. Design-Retrospective study in a metabolic investigation unit. Patients-28 patients with a respiratory chain disorder identified from biochemical or genetic analyses, or both, and 133 age matched controls. Controls were children in whom causes of secondary hyperlactataemia and/or disorders, aVecting the energy pathways could be excluded. Methods-Lactate and pyruvate were measured in blood, together with other intermediary metabolism indices, before and one hour after four meals each day. Lactate and creatinine in a 24 hour urine sample collected at the same time were analysed. When basal hyperlactataemia was not evident, an intravenous glucose or pyruvate loading test was performed as a provocative test. Results-Abnormal lactate metabolism was found in 25 of 28 patients thus demonstrating the potential usefulness of these investigations in the diagnosis of mitochondrial diseases. Moderate lactate accumulation was present in relatively mild disease, associated with a mitochondrial DNA mutation and combined respiratory complexes deficiency. By contrast, high lactate concentrations were observed in very young children, with severe disease, isolated complex deficiency, and no apparent mitochondrial DNA defect.

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Section: Methodsmentioning

confidence: 99%

In vivo functional investigations of lactic acid in patients with respiratory chain disorders

Touati

Rigal

Lombès

et al. 1997

Archives of Disease in Childhood

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“…The frequency of either inherited or acquired (somatic) mtDNA mutation is surprisingly high, reflecting vulnerability to replication errors and susceptibility to damaging reactive molecules confounded by limited DNA repair mechanisms. Diseases caused by mtDNA mutations were first described in 1988 [2–5]. Since then over 700 mutations, both germline and somatic, have been identified, some of which have been associated with human disorders including myopathies, neurodegenerative diseases, diabetes, cancer and infertility (http://www.mitomap.org/bin/view.pl/MITOMAP/WebHome).…”

Section: Mitochondrial Dna and Its Role In Pathologiesmentioning

confidence: 99%

Mitochondrial replacement therapy in reproductive medicine

Wolf¹,

Mitalipov²,

Mitalipov³

2015

Trends in Molecular Medicine

152

113

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Mitochondrial dysfunction is implicated in disease and in age-related infertility. Mitochondrial replacement therapies (MRT) in oocytes or zygotes such as pronuclear (PNT), spindle (ST) or polar body (PBT) transfer could prevent second generation transmission of mitochondrial DNA (mtDNA) defects. PNT, associated with high levels of mtDNA carryover in mice but low levels in human embryos, carries ethical issues secondary to donor embryo destruction. ST, developed in primates, supports normal development to adults and low mtDNA carryover. PBT in mice, coupled with PN or ST, may increase the yield of reconstructed embryos with low mtDNA carryover. MRT also offers replacement of the deficient cytoplasm in oocytes from older patients, with the expectation of high pregnancy rates following in vitro fertilization.

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“…MtDNA deletions are frequently associated with three syndromes: Pearson syndrome, Kearns-Sayre syndrome (KSS), and chronic progressive external ophthalmoplegia (cPEO) (Zeviani et al, 1988;Moraes et al, 1989;Rotig et al, 1990). Moreover, many studies have shown that mtDNA deletions accumulate with aging and are mainly linked to nervous system disorders (Cortopassi et al, 1992;Bender et al, 2006;Kraytsberg et al, 2006).…”

Section: Deletionsmentioning

confidence: 99%

Mitochondrial DNA-related disorders: emphasis on mechanisms and heterogeneity

Cagin¹,

Enrı́quez²

2015

Turk J Biol

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IntroductionMitochondria are the organelles with the main responsibility for energy production in cells, generated in the form of ATP by oxidative phosphorylation (OXPHOS). Mitochondria are additionally involved in many other important processes, including apoptosis and calcium homeostasis (Pozzan et al., 2000;Newmeyer and Ferguson-Miller, 2003). Furthermore, mitochondria are the main site of the production of reactive oxygen species (ROS). The tricarboxylic acid (TCA) cycle, which in addition to its contribution to ATP production also generates several important metabolic intermediates, occurs in mitochondria (Boveris et al., 1972).Mitochondria contain their own genetic material, called mitochondrial DNA (mtDNA), a 16,569-bp-long, doublestranded, circular molecule containing just 37 genes. Only 13 of these genes encode proteins, all of them contributing to the formation of OXPHOS complexes through association with nuclear DNA (nDNA)-encoded proteins. The remaining genes encode 22 tRNAs and 2 rRNAs (Anderson et al., 1981). The copy number of mtDNA varies depending on the cell type and energy demand of the tissue.Replication of mtDNA is dependent on proteins encoded by nDNA and imported to mitochondria. Therefore, mtDNArelated diseases can be caused not only by mutations in mtDNA but also by defects in nDNA-encoded factors required for mtDNA replication (Figure 1). This dualdependence of mtDNA integrity is largely responsible for the heterogeneous nature of mtDNA-related diseases.The history of research on mtDNA-related diseases is relatively short, with the first disease-causing mtDNA mutations reported in 1988 (Holt et al., 1988;Wallace et al., 1988). These two ground-breaking studies paved the way to the discovery and characterization of a large number of mtDNA mutations, and at least 300 pathogenic mtDNA mutations have now been identified (www.mitomap.org). Due to the high degree of heterogeneity in mtDNA-related diseases, it is very hard to quantify their prevalence. Studies have been conducted to define the severity of mtDNA mutations in specific populations; however, a worldwide study in this field is missing. A study based in northeastern England reported that mtDNA-related diseases occurred at a frequency of 1 in 10,000 in working-age adults with a further 1 in 6000 people (below retirement age) at Abstract: Mitochondrial diseases are a heterogeneous group of disorders that are currently the focus of intense research. The many cell functions performed by mitochondria include ATP production, calcium homeostasis, and apoptosis. One of the unique properties of mitochondria is the existence of a separate mitochondrial genome (mitochondrial DNA, mtDNA) found in varying copy numbers and containing 37 genes, 13 of them encoding proteins. All 13 mitochondrially encoded proteins form part of oxidative phosphorylation complexes through combination with approximately 100 nuclear DNA-encoded proteins. Coregulation of nDNA and mtDNA is therefore essential for mitochondrial function, and this coregulation contributes t...

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Deletions of mitochondrial DNA in Kearns‐Sayre syndrome

Cited by 468 publications

References 4 publications

In vivo functional investigations of lactic acid in patients with respiratory chain disorders

In vivo functional investigations of lactic acid in patients with respiratory chain disorders

Mitochondrial replacement therapy in reproductive medicine

Mitochondrial DNA-related disorders: emphasis on mechanisms and heterogeneity

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