Chronic atrial fibrillation associated with somatic mitochondrial DNA mutations in human atrial tissue

Abstract

premature stop codon 91 amino acids downstream from the last original amino acid (Ala 227). This mutation resulted in the subsequent generation of a non-functional short polypeptide (318 amino acids) that lacks its intracellular C-terminal region or well in a null allele. In this region, URAT1 directly interacts with PDZK1, a PDZ domain-containing protein that interacts with several membrane proteins through its PDZ motif.11 PDZK1 regulates the functional activity of URAT1-mediated urate transport in the apical membrane of renal proximal tubule. 12 The association of URAT1 with PDZK1 enhances urate transport activities in HEK293 cells (1.4-fold), and the deletion of the patient lacks its PDZ domain. The 680Gins was not present in 240 chromosomes of normal individuals, so it is likely that his abnormal allele represents rare polymorphisms. On the other hand, primary gout phenotype of our patient is not due to this kind of mutation. Our finding that the N-terminus region of the SLC22A12 gene seems to be associated with reduced renal uric acid is worth mentioning.

Metabolic Considerations in Atrial Fibrillation ― Mechanistic Insights and Therapeutic Opportunities ―

“…35 On the other hand, AF patients have increased mtDNA mutation rates and evidence of atrial oxidative injury. 36 In patients undergoing cardiac surgery (22 children/adolescents and 66 adults), mtDNA deletions were increased in the adult AF patients compared with those in sinus rhythm. Pediatric and adolescent patients did not show mtDNA deletions; thus, mtDNA deletion seems to be associated with aging.…”

The Contradictory Genetics of Atrial Fibrillation: The Growing Gap Between Knowledge and Clinical Implications

“…Thanks to a remarkable resequencing effort in selected cohorts, at least 12 ion channels (alpha and beta subunits) and 3 nonion channels genes causing or predisposing to AF have been identified. Furthermore, GWAS studies demonstrated the existence of multiple AF risk loci (>10) and mitochondrial DNA mutations have been found to have a causative role in some cases . However, it is also true that the identification of families in which AF is indisputably distributed in a Mendelian fashion is rare, and cohort molecular screening studies have identified mutation only in a small fraction of cases with limited clinical implications …”

“…Furthermore, GWAS studies demonstrated the existence of multiple AF risk loci (>10) 6 and mitochondrial DNA mutations have been found to have a causative role in some cases. 7,8 However, it is also true that the identification of families in which AF is indisputably distributed in a Mendelian fashion is rare, and cohort molecular screening studies have identified mutation only in a small fraction of cases with limited clinical implications. 9 So there is a clear discrepancy between the richness of identified genetic causes and the power of genetic testing to identify successfully the genetic defect when the screening is "clinically driven."…”

Effects of exercise intensity on copy number and mutations of mitochondrial DNA in gastrocnemus muscles in mice

“…The displacement loop (D-loop) region is the major control site for mtDNA replication and transcription (3). The D-loop region is increasingly susceptible to oxidative damage and electrophilic attack (4,5), thus it is more prone to mutation. It has been acknowledged that exercise causes an increase in the skeletal muscle mitochondrial enzyme content and activity (6).…”

“…It has been acknowledged that exercise causes an increase in the skeletal muscle mitochondrial enzyme content and activity (6). Perturbations in mitochondrial content and function have been linked to a wide variety of diseases in multiple tissues, and exercise may serve as a potent approach by which to prevent and treat these pathologies (5). However, no study has been conducted to evaluate the association effects of exercise on mtDNA content and mutations.…”