The role of control region mitochondrial DNA mutations in cardiovascular disease: stroke and myocardial infarction

Abstract

Recent studies associated certain type of cardiovascular disease (CVD) with specific mitochondrial DnA (mtDnA) defects, mainly driven by the central role of mitochondria in cellular metabolism. considering the importance of the control region (cR) on the regulation of the mtDnA gene expression, the aim of the present study was to investigate the role of mtDnA cR mutations in two CVDs: stroke and myocardial infarction (MI). MtDNA CR mutations (both fixed and in heteroplasmy) were analysed in two demographically-matched case-control samples, using 154 stroke cases, 211 MI cases and their corresponding control individuals. Significant differences were found, reporting mutations m.16145 G > A and m.16311 T > c as potential genetic risk factors for stroke (conditional logistic regression: p = 0.038 and p = 0.018, respectively), whereas the m.72 T > C, m.73 A > G and m.16356 T > C mutations could act as possible beneficial genetic factors for MI (conditional logistic regression: p = 0.001, p = 0.009 and p = 0.016, respectively). Furthermore, our findings also showed a high percentage of point heteroplasmy in Mi controls (logistic regression: p = 0.046; OR = 0.209, 95% CI [0.045-0.972]). These results demonstrate the possible role of mtDNA mutations in the CR on the pathogenesis of stroke and Mi, and show the importance of including this regulatory region in genetic association studies. Cardiovascular disease (CVD) is one of the most widespread and common causes of death in the world. The onset and severity of these diseases are influenced by both genetic and environmental factors. Recent evidences associate mitochondrial dysfunction with several cardiovascular manifestations, mainly driven by the central role of mitochondria in cellular metabolism, particularly in energetically demanding tissues such as brain and heart 1,2. Human mitochondrial DNA (mtDNA) is 16.6-kb double-stranded circular DNA molecule that encodes for 13 electron transport chain (ETC) proteins, 2 ribosomal RNAs (rRNAs) and 22 transports RNAs (tRNAs). The control region (CR) encompasses the light and heavy strand promoters, the heavy strand origin of replication (O H), three conserved sequence blocks and the termination associated sequences (TAS) 3. MtDNA is more susceptible than nuclear DNA to oxidative damage, probably due to the lack histone complex and an inefficient DNA repair mechanisms, which may serve as a protective barrier against external and internal noxious agents as reactive oxygen species (ROS) 4. However, the hypothesis of direct damage by ROS is increasingly criticized and it is suggested that errors in mtDNA replication and repair may be the main cause of its high mutation rate (~10-fold greater than in nDNA) 5. Recent evidence have linked certain CVDs with specific mtDNA mutations including base substitutions 6-11 , deletions 12 , duplications 13 and point or length heteroplasmy 14-17 both in coding 6,9,10,12,14,15 and noncoding reg ion 6-9,11,13,16,17 of mtDNA. In particular, mtDNA mutations located in CR have a potential importanc...

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“…In this study, however, only mtDNA variants were explored, and hence there was no accounting for population stratification. In another study, control-region (D-loop) variants m.16145 G > A and m.16311 T > C were found to be potential risk factors for stroke ( p -value = 0.038 and p -value = 0.018, respectively) [ 101 ]. It should be noted that there is no mention of multiple-testing correction in this study, only the variants within the mitochondrial D-loop were considered, and there is no accounting for population stratification.…”