Mitochondrial respiratory chain complex I is an important component of the oxidative respiratory chain, with the mitochondrially encoded NADH:ubiquinone oxidoreductase core subunit 1 (MT-ND1) being one of the core subunits. MT-ND1 plays a role in the assembly of complex I and its enzymatic function. MT-ND1 gene mutation affects pathophysiological processes, such as interfering with the early assembly of complex I, affecting the ubiquinone binding domain and proton channel of complex I, and affecting oxidative phosphorylation, thus leading to the occurrence of diseases. The relationship between MT-ND1 gene mutation and disease has been has received increasing research attention. Therefore, this article reviews the impact of MT-ND1 mutations on disease progression, focusing on the impact of such mutations on diseases and their possible mechanisms, as well as the application of targeting MT-ND1 gene mutations in disease diagnosis and treatment. We aim to provide a new perspective leading to a more comprehensive understanding of the relationship between MT-ND1 gene mutations and diseases.

Mutations in mitochondrial tRNA (mt-tRNA) are the important causes for maternally inherited hypertension, however, the pathophysiology of mt-tRNA mutations in clinical expression of hypertension remains poorly understood.

In this study, we report the molecular features of a Han Chinese pedigree with maternally transmitted essential hypertension. The entire mitochondrial genomes are PCR amplified and sequenced, Moreover, phylogenetic analysis, haplogroup analysis, as well as pathogenicity scoring system are used to assess the potential roles for mtDNA mutations.

Strikingly, among ten matrilineal relatives, three of them suffer from variable degree of hypertension at different age at onset. Sequence analysis of the complete mitochondrial genomes suggests the presence of three possible pathogenic mtDNA mutations: tRNAAsp T7561C, tRNAHis C12153T and A12172G, together with a set of variants belonging to East Asian mitochondrial haplogroup M7a. Interestingly, the T7561C mutation occurs at position 44 in the variable region of tRNAAsp, while the C12153T and A12172G mutations are localized at extremely conserved nucleotides in the D-arm and anticodon stem of tRNAHis gene, respectively, which are critical for tRNA steady-state level and function.

Mitochondrial T7561C, C12153T and A12172G mutations may lead to the failure in tRNAs metabolism, and cause mitochondrial dysfunction that is responsible for hypertension. However, the homoplasmy form of mt-tRNA mutations, incomplete penetrance of hypertension suggest that T7561C, C12153T and A12172G mutations are insufficient to produce the clinical phenotype, hence, other risk factors such as environmental factors, nuclear genes and epigenetic modifications may contribute to the phenotypic manifestation of maternally inherited hypertension in this Chinese pedigree.

Mutations in mitochondrial DNA (mtDNA) are the most important causes for Leber's hereditary optic neuropathy (LHON). Of these, three primary mtDNA mutations account for more than 90% cases of this disease. However, to date, little is known regarding the relationship between mitochondrial tRNA (mt-tRNA) variants and LHON.

In this study, we aimed to investigate the association between mt-tRNA variants and LHON.

One hundred thirty-eight LHON patients lacking three primary mutations (ND1 3460G > A, ND4 11778Gxs > A, and ND6 14484 T > C), as well as 266 controls were enrolled in this study. PCR-Sanger sequencing was performed to screen the mt-tRNA variants. Moreover, the phylogenetic analysis, pathogenicity scoring system, as well as mitochondrial functions were performed.

We identified 8 possible pathogenic variants: tRNA^Phe 593 T > C, tRNA^Leu(UUR) 3275C > T, tRNA^Gln 4363 T > C, tRNA^Met 4435A > G, tRNA^Ala 5587 T > C, tRNA^Glu 14693A > G, tRNA^Thr 15927G > A, and 15951A > G, which may change the structural and functional impact on the corresponding tRNAs, and subsequently lead to a failure in tRNA metabolism. Furthermore, significant reductions in mitochondrial ATP and MMP levels and an overproduction of ROS were observed in cybrid cells containing these mt-tRNA variants, suggesting that these variants may lead to mitochondrial dysfunction which was responsible for LHON.

Our study indicated that mt-tRNA variants were associated with LHON, and screening for mt-tRNA variants were recommended for early detection, diagnosis, and prevention of maternally inherited LHON.

Essential hypertension (EH) is one of the most common cardiovascular diseases worldwide, entailing a high level of morbidity. EH is a multifactorial disease influenced by both genetic and environmental factors, including mitochondrial DNA (mtDNA) genotype. Previous studies identified mtDNA mutations that are associated with maternally inherited hypertension, including tRNA^Ile m.4263A>G, m.4291T>C, m.4295A>G, tRNA^Met m.4435A>G, tRNA^Ala m.5655A>G, and tRNA^Met/tRNA^Gln m.4401A>G, et al. These mtDNA mutations alter tRNA structure, thereby leading to metabolic disorders. Metabolic defects associated with mitochondrial tRNAs affect protein synthesis, cause oxidative phosphorylation defects, reduced ATP synthesis, and increase production of reactive oxygen species. In this review we discuss known mutations of tRNA genes encoded by mtDNA and the potential mechanisms by which these mutations may contribute to hypertension.

Mutations in mitochondrial DNA, especially in mitochondrial tRNA (mt-tRNA) genes, are the important causes for maternally inherited hypertension. In this study, we reported the clinical, genetic, and molecular characterization of a Han Chinese family with hypertension. Most strikingly, this family exhibited a high penetrance and expressivity of hypertension. Sequence analysis of the complete mt-tRNA genes showed the presence of tRNA^Met A4435G and tRNA^Ala C5601T mutations. The A4435G had already been reported as a pathogenic mutation associated with hypertension; in addition, the C5601T mutation, which was located at the highly conserved nucleotide of T arm of tRNA^Ala, created a novel Watson-Crick base pairing and may result in failure of tRNA metabolism. Moreover, bioinformatics analysis indicated that the C5601T mutation altered the secondary structure of tRNA^Ala. Thus, the mitochondrial dysfunction, caused by the A4435G mutation, may be worsened by the C5601T mutation. Taken together, our data indicated that the co-occurrence of the A4435G and C5601T mutations may account for the high penetrance and expressivity of hypertension in this family. Therefore, our study provided novel insight into the pathophysiology of maternally inherited hypertension.

Mitochondrial DNA (mtDNA) mutations are associated with cardiovascular disease, including hypertension (HTN). Here we performed a genetic and molecular analysis of 13 mtDNA-encoded subunits of respiratory chain complexes in 100 Chinese Han and 80 Mongolian HTN cases, and 100 Han and 42 Mongolian normotension subjects. The total cholesterol of the Mongolian normotensive subjects was higher than that of the Han normotensive group (p < .05). Sequence analysis identified 636 point mutations in the 13 mtDNA-encoded subunits in the Han and Mongolian hypertensive individuals, including 66 in NADH dehydrogenase subunit 1(ND1), 62 in ND2, 71 in COI, 29 in COII, 17 in ATP8, one in ATP6/8, 49 in ATP6, 27 in COIII, 27 in ND3, 14 in ND4L, 74 in ND4, 97 in ND5, 24 in ND6, and 78 in CYTB. Eight of these point mutations were present at significantly different frequencies in Han and Mongolian hypertensive individuals. Thirty-one point mutations were present only in Mongolian hypertensive individuals, while 73 were present only in Han hypertensive individuals. The relation between point mutations in 13 mtDNA-encoded subunits of respiratory chain complexes and HTN is worth to further research in future; however, the functional effects of these mutations require elucidation.

To investigate the relationship between mitochondrial DNA (mtDNA) and hypertension as well as the mechanism involved in mitochondrial metabolic dysfunction. We identified a novel tRNAMet C4467A mutation in a Han Chinese family with hypertension. The maternal members presented with increased glucose, total cholesterol, low-density lipoprotein, and serum sodium as well as decreased potassium compared with non-maternal members (P < 0.05). Segregation analysis showed this mutation was maternally inherited. We analyzed lymphocyte cell lines derived from three maternal and three non-maternal family members. Reactive oxygen species production in the mutant cell lines was 114.5% higher compared with that in controls (P < 0.05) while ATP was 26.4% lower. The mitochondrial membrane potential of the mutated cell lines was 26.2% lower than that in controls (P < 0.05). Oxygen consumption rates were decreased in the mutant cell lines (P < 0.05). The activation of caspase-3/7 was 104.1% higher in the mutant cell lines compared with controls (P < 0.05). The expression of voltage-dependent anion channel (VDAC), Bax and apoptosis-inducing factor (AIF) in the mutant cell lines was higher compared with that in controls, with the increased colocalization of VDAC and Bax. Therefore, this mutation contributes to oxidative stress and mitochondrial biogenesis dysfunction, which may be involved in the pathogenesis of hypertension.

Mutations in mitochondrial (mt)transfer (t)RNA (mt‑tRNA) have been reported to serve important roles in hypertension. To determine the underlying molecular mechanisms of mt‑tRNA mutations in hypertension, the present study screened for mt‑tRNA mutations in a Chinese family with a high incidence of essential hypertension. Sequence analysis of the mt‑tRNA genes in this family revealed the presence of an A4401G mutation in the glycine‑and methionine‑tRNA genes, and a G5821A mutation in the cysteine‑tRNA (tRNACys) gene. The G5821A mutation was located at a position conserved in various species, and disrupted G6‑C67 base‑pairing. It was hypothesized that the G5821A mutation may decrease the baseline expression levels of tRNACys, and consequently result in failure of tRNA metabolism. The A4401G mutation was reported to cause the mitochondrial dysfunction responsible for hypertension. Thus, the combination of G5821A and A4401G mutations may contribute to the high incidence of hypertension in this family. Mt‑tRNA mutations may serve as potential biomarkers for hypertension.

Hypertension is a very important risk factor for cardiac vascular disease. The previous studies showed that mitochondrial DNA mutations are associated with cardiovascular disease, including hypertension.

In this study we did systematical analysis on the total 22 mitochondrial tRNAs and the clinical, genetic and molecular changes of 140 Chinese hypertension and 124 controls.

This analysis identified 22 nucleotide changes among 15 different tRNA genes. There are 15 mutations with CI (Conservation index) larger than 75%. Of these, there are 26 patients with CI larger than 75% in the HTN group, higher than the 6 subjects in the control group (P=0.00). The tRNA(Phe) G586A, tRNA(Lys) G8313A and tRNA(His) G12147A mutations create highly conservative base-pairings on the D-stem, tRNA(Lys) G8342A on the T-stem, tRNA(Phe) T616C, tRNA(Ala) T5628C, tRNA(Tyr) G5856A and tRNA(Thr) A15924G on the AC stem, tRNA(Leu(CUN)) G12300A on the AC loop, tRNA(Met) C4467T, tRNA(Trp) T5578C, tRNA(Lys) A8296G, tRNA(Arg) T10463C and tRNA(Thr) C15891T on ACC stem, and tRNA(Ser(UCN)) C7492T on D-A junction, while the other tRNA variants were polymorphisms. The pedigrees of PLAH78 carrying the T5578C, PLAH84 carrying the C4467T, PLAH60 carrying the T5628C and PLAH118 carrying the C7492T mutation exhibited maternal transmission of essential hypertension. Sequence analysis of their mitochondrial genomes revealed the presence of T5578C, C4467T, T5628C or C7492T mutations but the absence of other functionally significant mutations in all matrilineal relatives of these families.

These tRNAs mutations, associated with altered structures of tRNAs and mitochondrial dysfunction, may contribute to the hypertension in Chinese population. A lot of work still should be done for the mechanism and functional effect of the mtDNA mutation on hypertension.

Mitochondrial DNA mutations may be associated with cardiovascular disease, including the common cardiac vascular disease, hypertension.

In this study we performed segregation analysis and systematically evaluated the entire mitochondrial genome in nine maternally inherited hypertension probands from Chinese Han families. We also performed clinical, genetic and molecular characterization of 74 maternally inherited members from these families and 216 healthy controls.

In the maternally inherited members, 12 had coronary heart disease (CHD), six had cerebrovascular disease, five had diabetes, nine had hyperlipidemia and three had renal disease. Laboratory tests showed that the sodium and potassium levels in blood of the maternally inherited members were higher than those of the control group (P < 0.01), while no differences were observed in fasting blood glucose (FBG), total cholesterol (TC), triglyceride, low density lipoprotein cholesterol (LDL-c) and creatinine levels (P > 0.05). The high density lipoprotein cholesterol (HDL-c) level of the maternally inherited members was lower than that of the control group (P = 0.04). The whole mitochondrial DNA sequence analysis revealed a total of 172 base changes, including 17 in ribosomal RNA (rRNA) genes, four in transfer RNA (tRNA) genes, and 22 amino acid substitutions. The remainder were synonymous changes or were located in non-coding regions. We identified seven amino acid changes in the nine maternally inherited hypertension families, including four mutations in ATPase6 and three in Cytb. More interestingly, tRNA(Ser(UCN)) 7492 T > C was absent in controls and was present in <1% of 2704 mtDNAs, indicating potential functional significance.

This study showed that mutations in mtDNA may contribute to the pathogenesis of hypertension in these Chinese Han families. In the near future, identification of additional mtDNA mutations may indicate further candidate genes for hypertension.

Mitochondrial dysfunction has been potentially implicated in both human and experimental hypertension. We performed the mutational analysis of tRNA(Lys) gene by PCR amplification and subsequent sequence analysis of the PCR fragments from 990 Chinese essential hypertensive subjects. We also made a comparative analysis of the collected data of the essential hypertension subjects who carried tRNA(Lys) mutation and those who did not carry the mutation using the methods of 1:1 case-control study. We totally found 7 mutation sites in 10 subjects. The onset ages of the individuals carrying the mutation were earlier than those who did not bear them. The level of blood urea nitrogen in hypertension subjects who carried tRNA(Lys) mutation was higher than the hypertension subjects who did not carried tRNA(Lys) mutation, while the serum potassium was significantly lower. The level of platelet count in hypertension subjects who carried tRNA(Lys) mutation was lower. The level of ventricular septal thickness in hypertension subjects who carried tRNA(Lys) mutation was higher and the level of left ventricular end diastolic diameter in hypertension subjects was significantly lower. Mitochondrial tRNA(Lys) mutations might result in the change of their structure and function, and then damaged the blood metabolism, the balance of the blood electrolyte, the steady-state of the blood cells and the heart structure and function, which were involved in the progress of the essential hypertension. Part of the essential hypertension patients clinically presented the characters of maternal inheritance, which might be associated with the tRNA(Lys) mutation.

Hypertension is a very common cardiovascular disease influenced by multiple genetic and environmental factors. More recently, there are some studies showed that mutations in mitochondrial DNA have been involved in its pathogenesis. In this study we did further investigations on this relationship.

Epidemiological research found a Han Chinese family with probable maternally transmitted hypertension. Sequence analysis of the whole mitochondrial DNA was detected from all the family members. And evaluations of the clinical, genetic and molecular characterization were also performed.

Matrilineal relatives within the family exhibited varying degrees of hypertension with an onset age of 48-55 years. Sequence analysis of this pedigree showed a novel homoplasmic 4329C > G mutation located at the 3' end of the tRNAIle and tRNAGln genes that was absent from 366 Chinese controls. The cytosine (C) at 4329 position was very important in the structural formation and stabilization of functional tRNAs, which was highly conserved in mitochondria of various organisms and also contributed to the high fidelity of the acceptor arm. Cells carrying this mutation were also shown to harbor mitochondrial dysfunctions.

The C4329G point mutation in tRNAIle and tRNAGln was involved in the pathogenesis of hypertension, perhaps in association with other modifying factors.

To examine whether the heteroplasmy level for 15059G>A mutation in the mitochondrial genome might be associated with essential hypertension.

This cross-sectional study involved 196 unrelated participants randomly selected from general population (90 males and 106 females) who underwent a regular medical check-up at the Institute for Atherosclerosis Research (Moscow, Russia). One hundred and twenty of them (61%) had essential hypertension, and 76 (39%) were apparently healthy normotensive persons. The level of heteroplasmy for 15059G>A mutation occurring in the coding region of cytochrome b gene (MT-CYB) of mtDNA isolated from the blood leukocytes, was quantified using DNA pyrosequencing method.

The 15059G>A heteroplasmy level ranged between 4% and 83%, with a median level of 31%. Between the upper and lower quartiles of 15059G>A heteroplasmy distribution, significant differences were observed for patients' age, systolic blood pressure, and triglyceride levels. 15059G>A heteroplasmy correlated both with age (r = 0.331, P < 0.001) and the presence of hypertension (r = 0.228, P = 0.002). Regression analysis revealed that the age explains 12% variability of 15059G>A heteroplasmy, and hypertension independently explains more 5% variability. The 15059G>A heteroplasmy exceeding 31% was found to be significantly associated with a higher risk of essential hypertension (odds ratio 2.76; P (Fisher) 0.019]. The study participants with high 15059G>A heteroplasmy level were found to have significantly higher age (P < 0.001) and the prevalence of essential hypertension (P = 0.033), as compared to those with low 15059G>A heteroplasmy level. These observations suggested a positive correlation between the level of 15059G>A heteroplasmy and essential hypertension.

This study provides the evidence of association of mtDNA 15059G>A mutation heteroplasmy with essential hypertension.

The long-term stress of high blood pressure levels increases the risk of a variety of macro- and microvascular complications of type 2 diabetes (T2D). The etiology of essential hypertension (EH) has been explored in depth, but the pathophysiology is multifactorial, complex, and poorly understood. Recent findings showed a role of inherited mutations in mitochondrial DNA (mtDNA) in maternally inherited forms of hypertension. However, an impact of somatic mtDNA mutations in the development of EH is significantly less investigated. In this study, we examined whether the level of heteroplasmy for the 15059G>A mutation in the mitochondrial cytochrome b gene is associated with EH in T2D.

The heteroplasmy level in mtDNA isolated from blood of 189 diabetic participants randomly selected from general population (124 of whom had EH) was quantified using a real-time PCR.

The 15059G>A heteroplasmy exceeding 39% was found to be significantly associated with a higher risk of EH (odds ratio 1.96; P (Fisher) 0.032).

There is the first evidence reporting association between the mtDNA 15059G>A mutation heteroplasmy and EH in T2D.

In this study, we investigated the effects of the voltage-dependent anion channel (VDAC) on the mitochondrial calcium cycle in cell lines carrying the mitochondrial DNA A4263G mutation. We established lymphoblastoid cell lines from three symptomatic individuals and one asymptomatic individual from the large Chinese Han family carrying the A4263G mutation; these were compared with three control cell lines. The mitochondrial Ca(2+) concentration and membrane potential were detected by loading cells with Rhod-2 and JC-1, respectively. Confocal images showed the average Rhod-2 and JC-1 fluorescence levels of individuals carrying the tRNA(Ile) A4263G mutation were lower than those of the control group (P<0.05). The baseline Rhod-2 fluorescence in the control group increased after exposure to atractyloside (an opener of the adenine nucleotide translocator, P<0.05), but no significant change was detected in the cell line harboring the A4263G mutation (P>0.05). The baseline JC-1 fluorescence in both the mutated and control cell lines decreased after subsequent exposure to atractyloside (P<0.05), whereas this effect of atractyloside was inhibited by Cyclosporin A (CsA, a VDAC blocker). We conclude that the mitochondrial VDAC is involved in both the increase of mitochondrial permeability to Ca(2+) and the decrease of mitochondrial membrane potential in cell lines carrying the mtDNA A4263G mutation.

We report here on the clinical, genetic, and molecular characterization of 1 Han Chinese family with maternally transmitted hypertension. Three of 7 matrilineal relatives in this 4-generation family exhibited the variable degree of essential hypertension at the age at onset, ranging from 35 to 60 years old. Sequence analysis of the complete mitochondrial DNA in this pedigree identified the novel homoplasmic 4401A>G mutation localizing at the spacer immediately to the 5' end of tRNA(Met) and tRNA(Gln) genes and 39 other variants belonging to the Asian haplogroup C. The 4401A>G mutation was absent in 242 Han Chinese controls. Approximately 30% reductions in the steady-state levels of tRNA(Met) and tRNA(Gln) were observed in 2 lymphoblastoid cell lines carrying the 4401A>G mutation compared with 2 control cell lines lacking this mutation. Failures in mitochondrial metabolism are apparently a primary contributor to the reduced rate of mitochondrial translation and reductions in the rate of overall respiratory capacity, malate/glutamate-promoted respiration, succinate/glycerol-3-phosphate-promoted respiration, or N,N,N',N'-tetramethyl-p-phenylenediamine/ascorbate-promoted respiration in lymphoblastoid cell lines carrying the 4401A>G mutation. The homoplasmic form, mild biochemical defect, late onset, and incomplete penetrance of hypertension in this family suggest that the 4401A>G mutation itself is insufficient to produce a clinical phenotype. Thus, the other modifier factors, eg, nuclear modifier genes and environmental and personal factors, may also contribute to the development of hypertension in these subjects carrying this mutation. These data suggest that mitochondrial dysfunctions, caused by the 4401A>G mutation, are involved in the development of hypertension in this Chinese pedigree.

Mitochondrial DNA mutations have been associated with cardiovascular disease. We report here the clinical, genetic, and molecular characterization of 1 Han Chinese family with suggestively maternally transmitted hypertension. Matrilineal relatives in this family exhibited the variable degree of hypertension at the age at onset of 44 to 55 years old. Sequence analysis of entire mitochondrial DNA in this pedigree identified the known homoplasmic 4435A>G mutation, which is located immediately at the 3 prime end to the anticodon, corresponding with the conventional position 37 of tRNA(Met), and 35 other variants belonging to the Asian haplogroup B5a. The adenine (A37) at this position of tRNA(Met) is extraordinarily conserved from bacteria to human mitochondria. This modified A37 was shown to contribute to the high fidelity of codon recognition, the structural formation, and stabilization of functional tRNAs. In fact, a 40% reduction in the levels of tRNA(Met) was observed in cells carrying the 4435A>G mutation. As a result, a failure in mitochondrial tRNA metabolism, caused by the 4435A>G mutation, led to approximately 30% reduction in the rate of mitochondrial translation. However, the homoplasmic form, mild biochemical defect, and late onset of hypertension in subjects carrying the 4435A>G mutation suggest that the 4435A>G mutation itself is insufficient to produce a clinical phenotype. The other modifier factors, such as nuclear modifier genes, environmental, and personal factors may also contribute to the development of hypertension in the subjects carrying this mutation. Our findings imply that the 4435A>G mutation may act as an inherited risk factor for the development of hypertension in this Chinese pedigree.