Abstract
Background
Mitochondrial DNA (mtDNA) mutations are associated with essential hypertension (EH), but the molecular mechanism remains largely unknown.
Objective
The aim of this study is to explore the association between mtDNA mutations and EH.
Methods
Two maternally inherited families with EH are underwent clinical, genetic and biochemical assessments. mtDNA mutations are screened by PCR-Sanger sequencing and phylogenetic, and bioinformatics analyses are performed to evaluate the pathogenicity of mtDNA mutations. We also generate cytoplasmic hybrid (cybrid) cell lines to analysis mitochondrial functions.
Results
Matrilineal relatives exhibit variable degree of clinical phenotypes. Molecular analysis reveals the presence of m.A14693G and m.A14696G mutations in two pedigrees. Notably, the m.A14693G mutation occurs at position 54 in the TψC loop of tRNAGlu, a position which is critical for post-transcriptionally modification of tRNAGlu. While the m.A14696G mutation creates a novel base-pairing (51C-64G). Bioinformatic analysis shows that these mutations alter tRNAGlu secondary structure. Additionally, patients with tRNAGlu mutations exhibit markedly decreased in mtDNA copy number, mitochondrial membrane potential (MMP) and ATP, whereas the levels of reactive oxygen species (ROS) increase significantly.
Conclusion
The m.A14696G and m.A14693G mutations lead to failure in tRNAGlu metabolism and cause mitochondrial dysfunction that is responsible for EH.
Abbreviations
EH, essential hypertension; mtDNA, mitochondrial DNA; cybrid, cytoplasmic hybrid; MMP, mitochondrial membrane potential; ROS, reactive oxygen species; mt-tRNA, mitochondrial tRNA; CHD, coronary heart disease; BP, blood pressure; CI, conservation index; MFE, minimum-free energy; H2DCFDA, 2’, 7’-Dichlorodihydrofluorescein diacetate; OXPHOS, oxidative phosphorylation; LHON, Leber’s hereditary optic neuropathy.
Data Sharing Statement
The datasets used and analyzed during the current study are available from corresponding author (Chun Wang, E-mail: [email protected]) on reasonable request.
Ethics Approval and Consent to Participate
This study was approved by the Ethics Committee of Mengcheng County Second People’s Hospital and conformed to the ethical principles of the Declaration of Helsinki. All participants from two pedigrees signed informed consent forms, as well as their cases to be published were obtained before participating in this study.
Acknowledgments
We are grateful to the members of two pedigrees for participating in this study.
Author Contributions
All authors contributed to data analysis, drafting or revising the article, have agreed on the journal to which the article will be submitted, gave final approval of the version to be published, and agree to be accountable for all aspects of the work.
Disclosure
No potential conflict of interest was reported by the author(s).