Mitochondrial biogenesis dysfunction and metabolic dysfunction from a novel mitochondrial tRNAMet 4467 C>A mutation in a Han Chinese family with maternally inherited hypertension.
Ontology highlight
ABSTRACT:
SUBMITTER: Liu Y
PROVIDER: S-EPMC5465199 | biostudies-literature | 2017 Jun
REPOSITORIES: biostudies-literature
Publications
Mitochondrial biogenesis dysfunction and metabolic dysfunction from a novel mitochondrial tRNA<sup>Met</sup> 4467 C>A mutation in a Han Chinese family with maternally inherited hypertension.
Liu Yuqi Y Li Yang Y Zhu Chao C Tian Liuyang L Guan Minxin M Chen Yundai Y
Scientific reports 20170608 1
To investigate the relationship between mitochondrial DNA (mtDNA) and hypertension as well as the mechanism involved in mitochondrial metabolic dysfunction. We identified a novel tRNA<sup>Met</sup> 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 mat ...[more]
Similar Datasets
Project description:We report here the clinical, genetic, and molecular characteristics of type 2 diabetes in a Chinese family. There are differences in the severity and age of onset in diabetes among these families. By molecular analysis of the complete mitochondrial genome in this family, we identified the homoplasmic m.15897G>A mutation underwent sequence analysis of whole mitochondrial DNA genome, which localized at conventional position ten of tRNAThr, and distinct sets of mtDNA polymorphisms belonging to haplogroup D4b1. This mutation has been implicated to be important for tRNA identity and stability. Using cybrid cell models, the decreased efficiency of mitochondrial tRNAThr levels caused by the m.15897G>A mutation results in respiratory deficiency, protein synthesis and assembly, mitochondrial ATP synthesis, and mitochondrial membrane potential. These mitochondrial dysfunctions caused an increase in the production of reactive oxygen species in the mutant cell lines. These data provide a direct evidence that a novel tRNA mutation was associated with T2DM. Thus, our findings provide a new insight into the understanding of pathophysiology of maternally inherited diabetes.
| S-EPMC7011485 | biostudies-literature
Project description:BackgroundCoronary heart disease (CHD) is the most common cause of mortality globally, yet mitochondrial genetic mutations associated with CHD development remain incompletely understood.MethodsThe subjects from three Chinese families with LHON underwent clinical, genetic, molecular, and biochemical evaluations. Biochemical characterizations included measuring the effects of the15910C > T mutation on tRNAThr levels, enzymatic activity of electron transport chain complexes, membrane permeability, and the mitochondria-mediated generation of both reactive oxygen species (ROS) and adenosine triphosphate (ATP).ResultsWe characterize mitochondrial genetic mutations in a three-generation Chinese family exhibiting signs of maternally inherited CHD. Of the 24 different family members in this pedigree we assessed, CHD was detected in 6, with variable severity and age of first appearance. When we sequenced the mitochondrial genomes of these individuals, we found a tRNAThr 15910C > T mutation of the Eastern Asian haplogroup M7b'c. This mutation is predicted to destabilize the strongly conserved (24C-10G) base-pairing, thereby disrupting tRNAThr functionality. When we performed Northern blotting, we detected we observed a 37.5% reduction in tRNAThr levels at baseline in cybrid cell lines bearing the 15910C > T mutation. When we conducted western blot analysis, we detected a ~ 24.96% decrease in mitochondrial translation rates in these same cells.ConclusionsIn the present report, Together these findings suggest a possible link between this 15910C > T tRNAThr mutation and CHD, potentially offering new avenues for future disease intervention.
| S-EPMC6912950 | biostudies-literature
Project description:BackgroundAlthough the mitochondrial DNA (mtDNA) mutations m.1555A > G and m.3243A > G are the primary causes of maternally inherited sensorineural hearing loss (SNHL), several other mtDNA mutations are also reported to be associated with SNHL.MethodsScreening of m.1555A > G and m.3243A > G mutations was performed for 145 probands. Nine probands fulfilled the following criteria: 1) bilateral and symmetric SNHL, 2) ≥ 4 family members with SNHL with a maternal trait of inheritance in ≥ 2 generations, 3) onset of SNHL before the age of 40 years, 4) high-frequency SNHL, and 5) no record of environmental factors related to SNHL. Sequencing of additional mtDNA regions was performed for five subjects meeting the clinical criteria, but the screening results were negative.ResultsAmong the nine cases meeting the five clinical criteria detailed above, three had the m.1555A > G mutation in MTRNR1, one had a m.3243A > G mutation in MTTL1, and one case had a m.7511T > C mutation in MTTS1. In the family with the m.7511T > C mutation, penetrance of SNHL among maternally related subjects was 9/17 (53%). The age at onset varied from birth (congenital) to adulthood. Hearing levels varied from normal to moderately impaired, unlike previously reported subjects with this mutation, where some maternal family members presented with profound SNHL. Family members with the m.7511T > C mutation and SNHL did not exhibit any specific clinical characteristics distinct from those of other individuals with SNHL and different mtDNA mutations. Among the 136 probands who did not meet the criteria detailed above, one case had the m.1555A > G mutation, and three cases had the m.3243A > G mutation.ConclusionsSince five of nine probands with the clinical criteria used in this study had mtDNA mutations, these criteria may be helpful for identification of candidate patients likely to have mtDNA mutations.
| S-EPMC5359870 | biostudies-literature
Project description:BackgroundSequence alternations in mitochondrial genomes, especially in genes encoding mitochondrial tRNA (mt-tRNA), were the important contributors to nonsyndromic hearing loss (NSHL); however, the molecular mechanisms remained largely undetermined.MethodsA maternally transmitted Chinese pedigree with NSHL underwent clinical, genetic, and biochemical assessment. PCR and direct sequence analyses were performed to detect mitochondrial DNA (mtDNA), GJB2, and SLC26A4 gene mutations from matrilineal relatives of this family. Mitochondrial functions including mitochondrial membrane potential (MMP), ATP, and ROS were evaluated in polymononuclear leukocytes (PMNs) derived from three deaf patients and three controls from this pedigree.ResultsFour of nine matrilineal relatives developed hearing loss at the variable age of onset. Two putative pathogenic mutations, m.5601C>T in tRNAAla and m.12311T>C in tRNALeu(CUN) , were identified via PCR-Sanger sequencing, as well as 34 variants that belonged to mtDNA haplogroup G2b2. Intriguingly, m.5601C>T mutation resided at very conserved nucleotide in the TψC loop of tRNAAla (position 59), while the T-to-C substitution at position 12311 located at position 48 in the variable stem of tRNALeu(CUN) and was believed to alter the aminoacylation and the steady-state level of tRNA. Biochemical analysis revealed the impairment of mitochondrial functions including the significant reductions of ATP and MMP, whereas markedly increased ROS levels were found in PMNs derived from NSHL patients with m.5601C>T and m.12311T>C mutations. However, we did not detect any mutations in GJB2 and SLC26A4 genes.ConclusionOur data indicated that mt-tRNAAla m.5601C>T and tRNALeu(CUN) 12311T>C mutations were associated with NSHL.
| S-EPMC8993639 | biostudies-literature
Project description:Mitochondrial respiratory chain disease represents one of the most common inborn errors of metabolism and is genetically heterogeneous, with biochemical defects arising from mutations in the mitochondrial genome (mtDNA) or the nuclear genome. As such, inheritance of mitochondrial respiratory chain disease can either follow dominant or recessive autosomal (Mendelian) inheritance patterns, the strictly matrilineal inheritance observed with mtDNA point mutations or X-linked inheritance. Parental consanguinity in respiratory chain disease is often assumed to infer an autosomal recessive inheritance pattern, and the analysis of mtDNA may be overlooked in the pursuit of a presumed nuclear genetic defect. We report the histochemical, biochemical and molecular genetic investigations of two patients with suspected mitochondrial disease who, despite being born to consanguineous first-cousin parents, were found to harbour well-characterised pathogenic mtDNA mutations, both of which were maternally transmitted. Our findings highlight that any diagnostic algorithm for the investigation of mitochondrial respiratory chain disease must include a full and complete analysis of the entire coding sequence of the mitochondrial genome in a clinically relevant tissue. An autosomal basis for respiratory chain disease should not be assumed in consanguineous families and that 'maternally inherited consanguineous' mitochondrial disease may thus be going undiagnosed.
| S-EPMC3230363 | biostudies-literature
Project description:The deafness-associated m.12201T>C mutation affects the A5-U68 base-pairing within the acceptor stem of mitochondrial tRNAHis The primary defect in this mutation is an alteration in tRNAHis aminoacylation. Here, we further investigate the molecular mechanism of the deafness-associated tRNAHis 12201T>C mutation and test whether the overexpression of the human mitochondrial histidyl-tRNA synthetase gene (HARS2) in cytoplasmic hybrid (cybrid) cells carrying the m.12201T>C mutation reverses mitochondrial dysfunctions. Using molecular dynamics simulations, we demonstrate that the m.12201T>C mutation perturbs the tRNAHis structure and function, supported by decreased melting temperature, conformational changes, and instability of mutated tRNA. We show that the m.12201T>C mutation-induced alteration of aminoacylation tRNAHis causes mitochondrial translational defects and respiratory deficiency. We found that the transfer of HARS2 into the cybrids carrying the m.12201T>C mutation raises the levels of aminoacylated tRNAHis from 56.3 to 75.0% but does not change the aminoacylation of other tRNAs. Strikingly, HARS2 overexpression increased the steady-state levels of tRNAHis and of noncognate tRNAs, including tRNAAla, tRNAGln, tRNAGlu, tRNALeu(UUR), tRNALys, and tRNAMet, in cells bearing the m.12201T>C mutation. This improved tRNA metabolism elevated the efficiency of mitochondrial translation, activities of oxidative phosphorylation complexes, and respiration capacity. Furthermore, HARS2 overexpression markedly increased mitochondrial ATP levels and membrane potential and reduced production of reactive oxygen species in cells carrying the m.12201T>C mutation. These results indicate that HARS2 overexpression corrects the mitochondrial dysfunction caused by the tRNAHis mutation. These findings provide critical insights into the pathophysiology of mitochondrial disease and represent a step toward improved therapeutic interventions for mitochondrial disorders.
| S-EPMC6983842 | biostudies-literature
Project description:AimsMaternally inherited diabetes and deafness (MIDD) is a complex disorder characterized by multiorgan clinical manifestations, including diabetes, hearing loss, and ophthalmic complications. This pilot study aimed to elucidate the intricate interplay between nuclear and mitochondrial genetics, epigenetic modifications, and their potential implications in the pathogenesis of MIDD.Main methodsA comprehensive genomic approach was employed to analyze a Sicilian family affected by clinically characterized MIDD, negative to the only known causative m.3243 A > G variant, integrating whole-exome sequencing and whole-genome bisulfite sequencing of both nuclear and mitochondrial analyses.Key findingsRare and deleterious variants were identified across multiple nuclear genes involved in retinal homeostasis, mitochondrial function, and epigenetic regulation, while complementary mitochondrial DNA analysis revealed a rich tapestry of genetic diversity across genes encoding components of the electron transport chain and ATP synthesis machinery. Epigenetic analyses uncovered significant differentially methylated regions across the genome and within the mitochondrial genome, suggesting a nuanced landscape of epigenetic modulation.SignificanceThe integration of genetic and epigenetic data highlighted the potential crosstalk between nuclear and mitochondrial regulation, with specific mtDNA variants influencing methylation patterns and potentially impacting the expression and regulation of mitochondrial genes. This pilot study provides valuable insights into the complex molecular mechanisms underlying MIDD, emphasizing the interplay between nucleus and mitochondrion, tracing the way for future research into targeted therapeutic interventions and personalized approaches for disease management.
| S-EPMC11324998 | biostudies-literature
Project description:Mitochondrial complex I-the largest enzyme complex of the mitochondrial oxidative phosphorylation machinery-has been proposed to contribute to a variety of age-related pathological alterations as well as longevity. The enzyme complex-consisting proteins are encoded by both nuclear (nDNA) and mitochondrial DNA (mtDNA). While some association studies of mtDNA encoded complex I genes and lifespan in humans have been reported, experimental evidence and the functional consequence of such variants is limited to studies using invertebrate models. Here, we present experimental evidence that a homoplasmic mutation in the mitochondrially encoded complex I gene mt-Nd2 modulates lifespan by altering cellular tryptophan levels and, consequently, ageing-related pathways in mice. A conplastic mouse strain carrying a mutation at m.4738C > A in mt-Nd2 lived slightly, but significantly, shorter than the controls did. The same mutation led to a higher susceptibility to glucose intolerance induced by high-fat diet feeding. These phenotypes were not observed in mice carrying a mutation in another mtDNA encoded complex I gene, mt-Nd5, suggesting the functional relevance of particular mutations in complex I to ageing and age-related diseases.
| S-EPMC6678443 | biostudies-literature
Project description:Maternally inherited mitochondrial respiratory disorders are rare, progressive, and multi-systemic diseases that remain intractable, with no effective therapeutic interventions. Patients share a defective oxidative phosphorylation pathway responsible for mitochondrial ATP synthesis, in most cases due to pathogenic mitochondrial variants transmitted from mother to child or to a rare de novo mutation or large-scale deletion of the mitochondrial genome. The clinical diagnosis of these mitochondrial diseases is difficult due to exceptionally high clinical variability, while their genetic diagnosis has improved with the advent of next-generation sequencing. The mechanisms regulating the penetrance of the mitochondrial variants remain unresolved with the patient's nuclear background, epigenomic regulation, heteroplasmy, mitochondrial haplogroups, and environmental factors thought to act as rheostats. The lack of animal models mimicking the phenotypic manifestations of these disorders has hampered efforts toward curative therapies. Patient-derived cellular paradigms provide alternative models for elucidating the pathogenic mechanisms and screening pharmacological small molecules to enhance mitochondrial function. Recent progress has been made in designing promising approaches to curtail the negative impact of dysfunctional mitochondria and alleviate clinical symptoms: 1) boosting mitochondrial biogenesis; 2) shifting heteroplasmy; 3) reprogramming metabolism; and 4) administering hypoxia-based treatment. Here, we discuss their varying efficacies and limitations and provide an outlook on their therapeutic potential and clinical application.
| S-EPMC7749081 | biostudies-literature
Project description:Mutations in mitochondrial DNA (mtDNA) have been associated with hypertension in several pedigrees with maternal inheritance. However, the pathophysiology of maternally inherited hypertension remains poorly understood. We reported here clinical, genetic evaluations and molecular analysis of mtDNA in a three-generation Han Chinese family with essential hypertension. Eight of 17 matrilineal relatives exhibited a wide range of severity in essential hypertension, whereas none of the offsprings of the affected father had hypertension. The age-at-onset of hypertension in the maternal kindred varied from 31 to 65 years, with an average of 52 years. Sequence analysis of mtDNA in this pedigree identified the known homoplasmic 4435A>G mutation, which is located at immediately 3' end to the anticodon, corresponding to the conventional position 37 of tRNA(Met), and 41 variants belonging to the Asian haplogroup G2a1. In contrast, the 4435A>G mutation occurred among mtDNA haplogroups B5a, D, M7a2 and J. 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, structural formation and stabilization of functional tRNAs. However, 41 other mtDNA variants in this pedigree were the known polymorphisms. The occurrence of the 4435A>G mutation in two genetically unrelated families affected by hypertension indicates that this mutation is involved in hypertension. Our present investigations further supported our previous findings that the 4435A>G mutation acted as an inherited risk factor for the development of hypertension. Our findings will be helpful for counseling families of maternally inherited hypertension.
| S-EPMC3198143 | biostudies-literature