Mitochondrial DNA 4977bp deletion mutation in peripheral blood reflects atrial remodeling in patients with non-valvular atrial fibrillation

PURPOSE: Recently, mitochondrial DNA 4977bp deletion (mtDNA4977-mut), a somatic mutation related to oxidative stress, has been shown to be associated with atrial fibrillation (AF). We hypothesized that patient age, as well as electroanatomical characteristics of fibrillating left atrial (LA), vary depending on the presence of mtDNA4977-mut in peripheral blood among patients with non-valvular AF. MATERIALS AND METHODS: Analyzing clinical and electroanatomical characteristics, we investigated the presence of the mtDNA4977-mut in peripheral blood of 212 patients (51.1±13.2 years old, 83.5% male) undergoing catheter ablation for non-valvular AF, as well as 212 age-matched control subjects. RESULTS: The overall frequency of peripheral blood mtDNA4977-mut in patients with AF and controls was not significantly different (24.5% vs. 19.3%, p=0.197). When the AF patient group was stratified according to age, mtDNA4977-mut was more common (47.4% vs. 20.0%, p=0.019) in AF patients older than 65 years than their age-matched controls. Among AF patients, those with mtDNA4977-mut were older (58.1±11.9 years old vs. 48.8±11.9 years old, p<0.001). AF patients positive for the mtDNA mutation had greater LA dimension (p=0.014), higher mitral inflow peak velocity (E)/diastolic mitral annular velocity (Em) ratio (p<0.001), as well as lower endocardial voltage (p=0.035), and slower conduction velocity (p=0.048) in the posterior LA than those without the mutation. In multivariate analysis, E/Em ratio was found to be significantly associated with the presence of mtDNA4977-mut in peripheral blood. CONCLUSION: mtDNA4977-mut, an age-related somatic mutation detected in the peripheral blood, is associated with advanced age and electro-anatomical remodeling of the atrium in non-valvular AF.ope

Das Auftreten der 4977 bp Deletion in Blut, Milz, Knochenmark und Skelettmuskel

Die 4977 bp Deletion (common deletion) ist die häufigste Deletion der mitochondrialen DNA. Ihr Auftreten wurde in vielen Vorarbeiten in verschiedenen Geweben detektiert. In dieser Arbeit wurde die Deletion im Gegensatz zu vielen Vorarbeiten bereits bei Personen unter 20 Jahren nachgewiesen. Dies gelang für alle untersuchen Gewebe (Milz, Knochenmark, Skelettmuskel und Blut). Mit dieser Untersuchung sollte überprüft werden, ob das Auftreten der 4977 bp Deletion als Prozess des Alterns selbst zu verstehen ist. Dies konnte nicht nachgewiesen werden. Lediglich im Skelettmuskelgewebe fand sich mit zunehmendem Alter ein relevanter Anstieg der 4977 bp Deletion. Wohingegen das relative Verhältnis von mitochondrialer DNA zur nukleären DNA konstant blieb. Für die untersuchten Blutproben ergaben sich ähnliche Ergebnisse. Es kam hier zu einer geringen Zunahme der Deletion im Bezug auf das Lebensalter, jedoch auch zu einer geringen Zunahme der mitochondrialen DNA bezüglich der nukleären DNA. Für Milz und Knochenmark konnte keine altersabhängige Zunahme der 4977 bp Deletion gefunden werden. Vielmehr zeigte sich, dass vermutlich ein vermehrtes Auftreten der 4977 bp Deletion schon in den Stammzellen und Vorläuferzellen ein vermehrtes Auftreten der Deletion im ausdifferenzierten Gewebe nach sich zog. In dieser Arbeit ist zu bemerken, dass das Extraktionverfahren keinen Einfluss auf die Qualität und die relative Quantität der dmtDNA, mtDNA und nDNA hat. Die 4977 bp- Deletion ist somit weniger als Alterungsprozess zu verstehen, vielmehr als Folge von verschiedenen Einflussfaktoren. Viele Arbeiten haben den Einfluss von exogenen Faktoren untersucht. Am wichtigsten scheint der Einfluss von oxidativen Prozessen auf das Auftreten der 4977 bp Deletion zu sein. Gründe hierfür sind die räumliche Nähe zu den oxidativen Prozessen der Mitochondrienmembran und die im Vergleich zu der nukleären DNA weniger ausgefeilten Reparaturmechanismen. Interindividuelle Unterschiede ergeben sich durch den Lifstyle (Alkohol- und Zigarettenkonsum) und individuellen Stress

Leigh Syndrome Spectrum: A Portuguese Population Cohort in an Evolutionary Genetic Era

Mitochondrial diseases are the most common inherited inborn error of metabolism resulting in deficient ATP generation, due to failure in homeostasis and proper bioenergetics. The most frequent mitochondrial disease manifestation in children is Leigh syndrome (LS), encompassing clinical, neuroradiological, biochemical, and molecular features. It typically affects infants but occurs anytime in life. Considering recent updates, LS clinical presentation has been stretched, and is now named LS spectrum (LSS), including classical LS and Leigh-like presentations. Apart from clinical diagnosis challenges, the molecular characterization also progressed from Sanger techniques to NGS (next-generation sequencing), encompassing analysis of nuclear (nDNA) and mitochondrial DNA (mtDNA). This upgrade resumed steps and favored diagnosis. Hereby, our paper presents molecular and clinical data on a Portuguese cohort of 40 positive cases of LSS. A total of 28 patients presented mutation in mtDNA and 12 in nDNA, with novel mutations identified in a heterogeneous group of genes. The present results contribute to the better knowledge of the molecular basis of LS and expand the clinical spectrum associated with this syndrome.info:eu-repo/semantics/publishedVersio

Mitochondrial DNA deletions in patients with esophagitis, Barrett’s esophagus, esophageal adenocarcinoma and squamous cell carcinoma

Background: Esophageal cancer is the eighth most common cancer globally. Esophageal adenocarcinoma (EA) and esophageal squamous-cell carcinoma (ESCC) are the two major types of esophageal cancer with poor prognosis. The mechanisms of the progression of normal esophagus to Barrett’s esophagus (BE) and EA are not fully understood. Mitochondria play a central role in generating energy, apoptosis and cell proliferation. Mutations of mitochondrial DNA (mtDNA) have been identified in many diseases including cancers. Mutations of mtDNA were investigated as a part of carcinogenesis.Objective: Our objective is to study whether the 5 kb and 7.4 kb mtDNA deletions are important in the progression of normal esophagus to BE and EA.Method: In this study, the frequency of the 5 kb and 7.4 kb deletions in mtDNA were studied in specimens ranging from nor- mal esophageal tissue to BE and EA and also from ESCC. Seventy six paraffin-embedded tissue samples were studied. Four couple primers were used.Results: Seventy-six tissue samples were analyzed total. The negative control and the positive control PCR product were detect- ed in all analyzed samples. The fusion PCR products, which represent the presence of the deletions, were not detected in any of the samples.Conclusion: We can say that, these deletions are not associated with progression of normal esophagus to BE and EA and they do not have an important role in detecting esophagitis, BE, EA, and ESSC.Keywords: Barrett's esophagus, esophageal cancer, mitochondrial DNA, 4977 bp, 7400 bp

Novel large-range mitochondrial dna deletions and fatal multisystemic disorder with prominent hepatopathy

Hepatic involvement in mitochondrial cytopathies rarely manifests in adulthood, but is a common feature in children. Multiple OXPHOS enzyme defects in children with liver involvement are often associated with dramatically reduced amounts of mtDNA. We investigated two novel large scale deletions in two infants with a multisystem disorder and prominent hepatopathy. Amount of mtDNA deletions and protein content were measured in different post-mortem tissues. The highest levels of deleted mtDNA were in liver, kidney, pancreas of both patients. Moreover, mtDNA deletions were detected in cultured skin fibroblasts in both patients and in blood of one during life. Biochemical analysis showed impairment of mainly complex I enzyme activity. Patients manifesting multisystem disorders in childhood may harbour rare mtDNA deletions in multiple tissues. For these patients, less invasive blood specimens or cultured fibroblasts can be used for molecular diagnosis. Our data further expand the array of deletions in the mitochondrial genomes in association with liver failure. Thus analysis of mtDNA should be considered in the diagnosis of childhood-onset hepatopathies