title: Evidence for the presence of somatic mitochondrial DNA mutations in right atrial appendage tissues of coronary artery disease patients.
abstract: Coronary artery disease (CAD) is a multifactorial disease with the underlying involvement of environment, life style and nuclear genetics. However, the role of extranuclear genetic material in terms of somatically acquired mutations in mitochondrial tRNA and protein coding genes in the initiation or progression of CAD is not well defined. Hence, in the present study, right atrial appendage tissues and matched blood samples of 150 CAD patients were screened for mutations in nucleotide regions encompassing the Cytochrome c oxidase subunit II (MT-CO2), tRNA lysine (MT-TK), ATP synthase F0 subunit 8 (MT-ATP8) and Cytochrome b (MT-CYB) genes of mitochondrial DNA. We have found 9 different somatic mutations in 6 % of the CAD patients. Out of these mutations, 4 each were localized in MT-TK gene (T8324A, A8326G, A8331G and A8344G) and MT-CYB genes (T15062C, C15238A, T15378G and C15491G) in addition to one mutation in non-coding region 7 (A8270T) of mitochondrial genome. In addition, we noticed that majority (85.3 %) of CAD patients showed double repeats of germ-line "CCCCCTCTA" intergenic sequence between MT-CO2 and MT-TK genes. Our in-silico investigations of missense mutations revealed that they may alter the free energy and stability of polypeptide chains of MT-CYB protein of complex III of mitochondrial respiratory chain. Based on our study findings, we hypothesize that the somatically acquired variations in MT-TK and MT-CYB genes may negatively impact the energy metabolism of cardiomyocytes in right atrial appendage tissues and contribute in the cardiac dysfunction among CAD patients. In conclusion, our findings may be likely to have potential implications in understanding the disease pathophysiology, diagnosis as well as for the better therapeutic management of CAD patients.
authors.affiliation: Department of Genetics & Molecular Medicine, Kamineni Hospitals, L B Nagar, Hyderabad, India, matamkavitha@gmail.com.
authors.forename: Kavitha
authors.initials: K
authors.lastname: Matam
authors.forename: Noor Ahmad
authors.initials: NA
authors.lastname: Shaik
authors.forename: Sunil
authors.initials: S
authors.lastname: Aggarwal
authors.forename: Sameer
authors.initials: S
authors.lastname: Diwale
authors.forename: Babajan
authors.initials: B
authors.lastname: Banaganapalli
authors.forename: Jumana Yousuf
authors.initials: JY
authors.lastname: Al-Aama
authors.forename: Ramu
authors.initials: R
authors.lastname: Elango
authors.forename: Pragna
authors.initials: P
authors.lastname: Rao
authors.forename: Qurratulain
authors.initials: Q
authors.lastname: Hasan
mesh_terms: D020517:Atrial Appendage; D001706:Biopsy; D003324:Coronary Artery Disease / Q000235:genetics*; D004272:DNA, Mitochondrial / Q000235:genetics*; D003576:Electron Transport Complex IV / Q000235:genetics; D005260:Female; D050259:Genes, Mitochondrial / Q000235:genetics; D054629:Genome, Mitochondrial / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000235:genetics; D008958:Models, Molecular; D009154:Mutation; D010085:Oxidative Phosphorylation; D058226:Plaque, Atherosclerotic / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: D004272:DNA, Mitochondrial; C117108:cytochrome C oxidase subunit II; D003576:Electron Transport Complex IV