Late-onset mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes syndrome with mitochondrial DNA 3243A>G mutation masquerading as autoimmune encephalitis:A case report

BACKGROUND Here,we present a unique case of mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes(MELAS)syndrome,which initially appeared to be autoimmune encephalitis and was ultimately confirmed as MELAS with the mitochondrial DNA 3243A>G mutation.CASE SUMMARY A 58-year-old female presented with acute-onset speech impediment and auditory hallucinations,symmetrical bitemporal lobe abnormalities,clinical and laboratory findings,and a lack of relevant prodromal history,which suggested diagnosis of autoimmune encephalitis.Further work-up,in conjunction with the patient’s medical history,family history,and lactate peak on brain lesions on magnetic resonance imaging,suggested a mitochondrial disorder.Mitochondrial genome analysis revealed the m.3243A>G variant in the MT-TL1 gene,which led to a diagnosis of MELAS syndrome.CONCLUSION This case underscores the importance of considering MELAS as a potential cause of autoimmune encephalitis even if patients are over 40 years of age,as the symptoms and signs are atypical for MELAS syndrome.

Peripheral mitochondrial DNA as a neuroinflammatory biomarker for major depressive disorder

In the pathogenesis of major depressive disorder, chronic stress-related neuroinflammation hinders favorable prognosis and antidepressant response. Mitochondrial DNA may be an inflammatory trigger, after its release from stress-induced dysfunctional central nervous system mitochondria into peripheral circulation. This evidence supports the potential use of peripheral mitochondrial DNA as a neuroinflammatory biomarker for the diagnosis and treatment of major depressive disorder. Herein, we critically review the neuroinflammation theory in major depressive disorder, providing compelling evidence that mitochondrial DNA release acts as a critical biological substrate, and that it constitutes the neuroinflammatory disease pathway. After its release, mitochondrial DNA can be carried in the exosomes and transported to extracellular spaces in the central nervous system and peripheral circulation. Detectable exosomes render encaged mitochondrial DNA relatively stable. This mitochondrial DNA in peripheral circulation can thus be directly detected in clinical practice. These characteristics illustrate the potential for mitochondrial DNA to serve as an innovative clinical biomarker and molecular treatment target for major depressive disorder. This review also highlights the future potential value of clinical applications combining mitochondrial DNA with a panel of other biomarkers, to improve diagnostic precision in major depressive disorder.

Mitochondrial DNA Mutations Associated with Aminoglycoside Ototoxicity

The mitochondrial 12S rRNA has been shown to be the hot spot for mutations associated with both aminoglycoside-induced and non-syndromic hearing loss. Of all the mutations, the homoplasmic A1555G and C1494T mutations at a highly conserved decoding region in the 12S rRNA have been associated with aminoglycoside-induced and non-syndromic hearing loss in many families worldwide. The A1555G or C1494T mutation is expected to form novel 1494C-G1555 or 1494U-A1555 base-pair at the highly conserved A-site of 12S rRNA. These transitions make the secondary structure of this RNA more closely resemble the corresponding region of bacterial 16S rRNA. Thus, the new U-A or G-C pair in 12S rRNA created by the C1494T or A1555G transition facilitates the binding of aminoglycosides, thereby accounting for the fact that the exposure to aminoglycosides can induce or worsen hearing loss in individuals carrying these mutations. Furthermore, the growth defect and impairment of mitochondrial translation were observed in cell lines carrying the A1555G or C1494T mutation in the presence of high concentration of aminoglycosides. In addition, nuclear modifier genes and mitochondrial haplotypes modulate the phenotypic manifestation of the A1555G and C1494T mutations. These observations provide the direct genetic and biochemical evidences that the A1555G or C1494T mutation is a pathogenic mtDNA mutation associated with aminoglycoside-induced and nonsyndromic hearing loss. Therefore, these data have been providing valuable information and technology to predict which individuals are at risk for ototoxicity, to improve the safety of aminoglycoside antibiotic therapy, and eventually to decrease the incidence of deafness.

Mitochondrial dysfunction and mitochondrial DNA mutations in atherosclerotic complications in diabetes

Mitochondrial DNA(mtDNA) is particularly prone to oxidation due to the lack of histones and a deficient mismatch repair system.This explains an increased mutation rate of mtDNA that results in heteroplasmy,e.g.,the coexistence of the mutant and wild-type mtDNA molecules within the same mitochondrion.In diabetes mellitus,glycotoxicity,advanced oxidative stress,collagen cross-linking,and accumulation of lipid peroxides in foam macrophage cells and arterial wall cells may significantly decrease the mutation threshold required for mitochondrial dysfunction,which in turn further contributes to the oxidative damage of the diabetic vascular wall,endothelial dysfunc-tion,and atherosclerosis.

Mitochondrial DNA mutations associated with aminoglycoside induced ototoxicity

Aminoglycosides(Am An) are widely used for their great efficiency against gram-negative bacterial infections. However, they can also induce ototoxic hearing loss, which has affected millions of people around the world. As previously reported, individuals bearing mitochondrial DNA mutations in the 12 S rRNA gene, such as m.1555A>G and m.1494C>T, are more prone to Am An-induced ototoxicity. These mutations cause human mitochondrial ribosomes to more closely resemble bacterial ribosomes and enable a stronger aminoglycoside interaction. Consequently,exposure to Am An can induce or worsen hearing loss in these individuals. Furthermore, a wide range of severity and penetrance of hearing loss was observed among families carrying these mutations. Studies have revealed that these mitochondria mutations are the primary molecular mechanism of genetic susceptibility to Am An ototoxicity, though nuclear modifier genes and mitochondrial haplotypes are known to modulate the phenotypic manifestation.

Implications of mitochondrial DNA mutations and mitochondrial dysfunction in tumorigenesis

Alterations in oxidative phosphorylation resulting from mitochondriai dysfunction have long been hypothesized to be involved in tumorigenesis. Mitochondria have recently been shown to play an important role in regulating both programmed cell death and cell proliferation. Furthermore, mitochondrial DNA （mtDNA） mutations have been found in various cancer cells. However, the role of these mtDNA mutations in tumorigenesis remains largely unknown. This review focuses on basic mitochondrial genetics, mtDNA mutations and consequential mitochondrial dysfunction associated with cancer. The potential molecular mechanisms, mediating the pathogenesis from mtDNA mutations and mitochondrial dysfunction to tumorigenesis are also discussed.

Complete mitochondrial DNA sequence analysis in two southern Chinese pedigrees with Leber hereditary optic neuropathy revealed secondary mutations along with the primary mutation

AIM: To investigate mitochondrial factors associated with Leber hereditary optic neuropathy (LHON) through complete sequencing and analysis of the mitochondrial genome of Chinese patients with this disease. METHODS: Two unrelated southern Chinese families with LHON and 10 matched healthy controls were recruited, and their entire mitochondrial DNA (mtDNA) was amplified and sequenced with the universal M13 primer. Then DNA sequence analysis and variation identification were performed by DNAssist and Chromas 2 software and compared with authoritative databases such as Mitomap. RESULTS: Mutational analysis of mtDNA in these two Chinese pedigrees revealed one common LHON-associated mutation, G11778A (Arg -> His), in the MT-ND4 gene. In addition, there were two secondary mutations in Pedigree 1: C34971 (Ala -> Val), and C3571T (Leu -> Phe) in the MT-ND1 gene, which have not been reported; and two secondary mutations occurred in Pedigree 2: A10398G (Thr -> Ala) in the MT-ND3 gene, and T14502C (Ile -> Val) in the MT-ND6 gene. Three polymorphisms, A73G, G94A and A263G in the mtDNA control region, were also found. CONCLUSION: Our study confirmed that the known MT-ND4* G11778A mutation is the most significant cause of LHON. The C3497T and C3571T mutations in Pedigree 1 were also both at hot-spots of MT-ND1; they may affect the respiratory chain in coordination with the primary mutation G11778A. In Pedigree 2, the two secondary mutations A10398G of MT-ND3 and T14502C of MT-ND6 may influence mitochondrial respiratory complex I, leading to the mitochondrial respiratory chain dysfunction which results in optic atrophy together with G11778A. Therefore, not only the common primary LHON mutation is responsible for the visual atrophy, but other secondary mtDNA mutations should also be considered when giving genetic counseling.

The Mitochondrial DNA Mutation at Position 11778 in Chinese Families with Leber's Hereditary Optic Neuropathy

We amplified the 340 bp of mitochondrial DMA (mtDNA) by PCR including the recognized sequence of restriction enzyme of SfaN I . After amplification and digestion of SfaN I , two bands of 190 bp and 150 bp appeared in the mtDNA of four normal individuals but only one band of 340 bp appeared in the mtDNA with the mutation of G to A at the site of the nucleotide 11778 because such mutation destroyed the recognized sequence of SfaN I . We studied the mtDNAs of the patients with Leber's hereditary optic neur...

Mutation in D-loop region of mitochondrial DNA in gastric cancer and its significance

AIM:To investigate the mutation in D-loop region of mitochondrial DNA in gastric cancer and its influence on the changes of reactive oxygen species (ROS) and cell cycle. METHODS: The D-loop region was amplified by PCR and sequenced.Reactive oxygen species and cell cycle were detected by flow cytometry in 20 specimens from gastric cancer and adjacent normal tissues.According to the sequence results,gastric cancer tissue was divided into mutation group and control group.Reactive oxygen species,apoptosis and proliferation in the two groups were compared. RESULTS:Among the 20 gastric cancer specimens, 18 mutations were identified in 7 patients,the mutation rate being 35%.There were four microsatellite instabilities in the mutations. No mutation was found in the adjacent tissues. Reactive oxygen species,apoptosis,and proliferation in the mutation group were all significantly higher than those in control group. CONCLUSION: Mutation in D-loop region plays a role in the genesis and development of gastric cancer.

A Study on the D-loop Region of Mitochondrial DNA (mtDNA) Mutation in Cervical Carcinomas

Objective Background-study on genesis and development of tumor is mainly concentrated on gene mutation in nucleus.In recent years,however,the role of mitochondrial DNA(mtDNA) mutation in tumor genesis has been given more and more attention,which is the only extra-nucleus DNA in cells of higher animals.Carcinoma of the uterine cervix is a common tumor in gynecology,but there are few reports of mtDNA mutation in this area.The focus of this study was to investigate the mtDNA mutation in tumor tissues of cervical carcinomas and their relationship to tumorigenesis and tumor development.Methods The D-loop region of 24 cervical carcinomas together with the adjacent normal tissues were amplified by PCR and sequenced.Results Among the 24 cervical carcinomas,30 mutations in 9 patients′ specimen were identified with the mutations rate of 37.5%(9/24).There were 8 microsatellite instabilities among the mutations and 13 new polymorphisms which were not reported previously in the Genbank.Conclusions The D-loop region of mitochondrial DNA is a highly polymorphoric and mutable region and the mutation rate is relatively high in patients with cervical carcinomas.

Molecular phylogenetics and population demographic history of Amphioctopus fangsiao,inferred from mitochondrial and microsatellite DNA markers

Amphioctopus fangsiao(Cephalopoda:Octopodidae)is an important commercial species in the coastal waters of China.In recent years,however,the resource of A.fangsiao have declined because of habitat destruction and overfishing.To analyze the genetic variations of A.fangsiao caused by the fluctuation of resources,the population genetic structure of nine sampling locations collected from the Bohai Sea to the South China Sea were investigated,using mtDNA COI fragments and microsatellite DNA.The results of F-statistics,AMOVA,STRUCTURE and PCA analyses showed three phylogeographic clades(Clades A,B and C),revealing limited genetic exchange between north and south populations.These clades diverged in 2.23(Clades A and B)and 3.67(Clades A,B and C)million years ago,during the dramatic environmental fluctuations,such as sea level and temperature changes,have exerted great influence on the survival distribution pattern of global organisms.Our results for low genetic connectivity among A.fangsiao populations provide insights into the development of management strategies,that is,to manage this species as separate management unit.

Mitochondrial DNA mutation in essential hypertension

Essential hypertension (EH) is an escalating problem for developed and developing countries.It is currently seen as a 'complex' genetic trait caused by multiple susceptibility genes which are modulated by gene-environment and gene-gene interactions.Over the past 10 years,mitochondrial defects have been implicated in a wide variety of degenerative diseases,aging,and cancer.Recently several studies showed that human essential hypertension has excess maternal transmission which suggests a possible mitochondrial involvement.However,the exact pathophysiology of mitochondrial DNA mutation (mtDNA) in essential hypertension still remains perplexing.With the application of a variety of imaging approaches and successive mouse model of mitochonddal diseases we convince that these problems will be resolved in the near future.(J Geriatr Cardiol 2008;5(1):60-64)

Mutations in the D-loop region of mitochondrial DNA in gastric cancer

Objective: To investigate the mutati ons in the D-loop region of mitochondrial DNA (mtDNA) in gastric cancer. Methods: The mtDNA of D-loop region was amplified by PCR and sequence d in 20 samples from gastric cancer tissue and adjacent normal membrane. Results: There were 7/20(35%) mutations in the mtDNA of D-loop regio n in gastric cancer patients. There were four microsatellite instabilities among the 18 mutations. Nine new polymorphisms were identified in 20 patients. Conclusion: The mtDNA of D-loop region might be highly polymorphoric and the mutation rate is high in patients with gastric cancer.

Study on 4977-bp deletion mutation of mitochondrial DNA in lung cancer

Objective: To study the 4977-bp deletion of mitochondiral DNA in lung cancer, adjacent normal tissue and health lung and its significance in the development of cancer. Methods:Thirty-seven matched lung cancer/adjacent histologically normal and 20 “true” normal lung tissue samples from patients without lung cancer were analyzed by long PCR technique. Results: Mitochondrial DNA 4977-bp deletion was detected in 54.1% (20/37) of lung cancers, 59.5% (22/37) of adjacent normal and 30.0% (6/30) of “true” normal lung tissues. The correlation of 4977-bp deletion with age and smoking factors was present in our data. Conclusion: Mitochondrial DNA 4977-bp deletion is not specific to lung cancer and unlikely to play an important role in carcinogenesis, and may only reflect the environmental and genetic influences during tumor progression.

Mutual promotion of mitochondrial fi ssion and oxidative stress contributes to mitochondrial-DNAmediated infl ammation and epithelial-mesenchymal transition in paraquat-induced pulmonary fibrosis

BACKGROUND:Pulmonary fibrosis(PF)is one of the main causes of death in patients with paraquat(PQ)poisoning.This study aimed to evaluate the relationship between mitochondrial fi ssion and oxidative stress in PQ-induced epithelial-mesenchymal transition(EMT)and PF.METHODS:C57BL/6 mice and MLE-12 cells were exposed to PQ to construct a PF model in vivo and in vitro.Histological changes in the lungs were examined by hematoxylin and eosin(H&E)staining.Mitochondrial morphology was detected by MitoTracker®Deep Red FM or transmission electron microscopy(TEM).Western blotting and immunofluorescence were used to determine the expression of protein.The migration ability of the cells was detected by the cell scratch test.Mitochondrial DNA(mtDNA)levels were assessed by real-time polymerase chain reaction(PCR).Enzyme-linked immunosorbent assay(ELISA)was applied to detect cytokine levels.Superoxide dismutase(SOD)activity and the levels of glutathione(GSH)and malondialdehyde(MDA)were detected by chemichromatometry.RESULTS:PQ exposure caused EMT and PF in vivo and in vitro.PQ destroyed mitochondrial structure and enhanced the expression of dynamin-related protein 1(Drp1),which were accompanied by oxidative stress.Inhibiting mitochondrial fission using mitochondrial division inhibitor-1(Mdivi-1),a selective inhibitor of Drp1,attenuated PQ-induced EMT and oxidative damage.Treatment with N-acetyl-L-cysteine(NAC),an antioxidant,reduced Drp1 expression,attenuated mitochondrial structure damage and inhibited PQ-induced EMT and PF.Both Mdivi-1 and NAC treatment markedly suppressed mtDNA release,the expression of Toll-like receptor 9(TLR9)and phosphorylation(P)-NF-κB p65 as well as cytokines(interleukin 6[IL-6],interleukin-1β[IL-1β],and tumor necrosis factor-α[TNF-α])production.CONCLUSION:Mutual promotion of mitochondrial fission and oxidative stress contributes to EMT in PQ-induced PF,which is associated with the mtDNA/TLR9/NF-κB pathway.

A color image encryption algorithm based on hyperchaotic map and DNA mutation

We devise a color image encryption scheme via combining hyperchaotic map,cross-plane operation and gene theory.First,the hyperchaotic map used in the encryption scheme is analyzed and studied.On the basis of the dynamics of hyperchaotic map,a color image encryption scheme is designed.At the end of the encryption process,a DNA mutation operation is used to increase the encoding images’randomness and to improve the encryption algorithm’s security.Finally,simulation experiments,performance analysis,and attack tests are performed to prove the effectiveness and security of the designed algorithm.This work provides the possibility of applying chaos theory and gene theory in image encryption.

Benchmark Dose Assessment for Coke Oven Emissions-Induced Mitochondrial DNA Copy Number Damage Effects

Objective The study aimed to estimate the benchmark dose(BMD)of coke oven emissions(COEs)exposure based on mitochondrial damage with the mitochondrial DNA copy number(mtDNAcn)as a biomarker.Methods A total of 782 subjects were recruited,including 238 controls and 544 exposed workers.The mtDNAcn of peripheral leukocytes was detected through the real-time fluorescence-based quantitative polymerase chain reaction.Three BMD approaches were used to calculate the BMD of COEs exposure based on the mitochondrial damage and its 95%confidence lower limit(BMDL).Results The mtDNAcn of the exposure group was lower than that of the control group(0.60±0.29 vs.1.03±0.31;P<0.001).A dose-response relationship was shown between the mtDNAcn damage and COEs.Using the Benchmark Dose Software,the occupational exposure limits(OELs)for COEs exposure in males was 0.00190 mg/m^(3).The OELs for COEs exposure using the BBMD were 0.00170 mg/m^(3)for the total population,0.00158 mg/m^(3)for males,and 0.00174 mg/m^(3)for females.In possible risk obtained from animal studies(PROAST),the OELs of the total population,males,and females were 0.00184,0.00178,and 0.00192 mg/m^(3),respectively.Conclusion Based on our conservative estimate,the BMDL of mitochondrial damage caused by COEs is0.002 mg/m^(3).This value will provide a benchmark for determining possible OELs.

Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes correlates with heteroplasmic mutations of mitochondrial DNA 3243 A single-case genealogy analysis

BACKGROUND： Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes （MELAS） is a common syndrome of mitochondrial diseases caused primarily by a mutation from adenine to guanine at mitochondrial DNA 3243. However, the correlation between heteroplasmic mutations and clinical characteristics of hereditary MELAS syndrome is unclear. OBJECTIVE： To survey the clinical behaviors, biochemical outcomes, and imaging data in a patient with suspected MELAS syndrome by maternal inheritance, and to investigate the correlation with heteroplasmic mutations of hemocyte mitochondrial DNA. DESIGN, TIME AND SETTING： A case analysis based on hereditary family surgery was performed in the Enliang Hospital of Anshan, Taian County, and biochemical tests and gene diagnosis were performed at the Department of Laboratory and Institute of Neurology, the First Affiliated Hospital of China Medical University, between March and September 2009. PARTICIPANTS： A 22-year-old female patient with MELAS syndrome was diagnosed in the First Affiliated Hospital of China Medical University in January, 2009. She had five males and seven females in her maternal family. METHODS： We obtained stroke and convulsion history in the patient and her family, as well as performing routine blood tests, plasma lactic acid levels before and after movement, and magnetic resonance of the head. A mutation at m.3243A 〉 G was verified using polymerase chain reaction-restriction fragment length polymorphism and DNA sequencing, and quantitated using real-time polymerase chain reaction. MAIN OUTCOME MEASURES： Correlation of clinical behaviors and biochemical outcomes, as well as imaging data with heteroplasmic mutations in family members with typical and atypical MELAS syndrome. RESULTS： Some family members had typical symptoms of convulsion, stroke, and MELAS syndrome, as well as atypical symptoms of microsomia, movement intolerance, febrile, and migraine. Magnetic resonance of the head was consistent with typical imaging data of MELAS syndrome during attacks, and family members showed cerebellar atrophy. A heteroplasmic mutation of mitochondrial DNA 3243 occurred in all family members, although higher levels caused severe typical symptoms. The age of first-onset convulsion was negatively correlated with level of heteroplasmic mutation （r = -0.852, P 〈 0.05）, but lactic acid was positively correlated with mutation levels （before movement, r = 0.945, P 〈 0.001; after movement, r= 0.945, P 〈 0.001）. CONCLUSION： MELAS syndrome was diagnosed in this family by maternal inheritance, and the etiological factor was a mutation of mitochondrial A3243G. The level of heteroplasmic mutation correlated with anticipated convulsion and lactic acid levels.

Inheritance of Chloroplast and Mitochondrial DNA in Chinese Fir (Cunninghamia lanceolata)

The inheritance of mitochondrial (mt) DNA and chloroplast (cp) DNA was investigated in intergeneric hybrids from crossing between Cunninghamia lanceolata (Lamb.) Hook. and Cryptomeria fortunei Hooibrenk. The chloroplast trnL trnF region and one intra genic segment of the mitochondrial gene, Cox Ⅲ, were amplified from those of the parents and hybrids by PCR using gene specific primers. Cp and mtDNA polymorphisms of the amplified regions were detected between the parents after restriction digestions. Restriction fragment length polymorphism (RFLP) analysis revealed that all the F 1 individuals possessed Cox Ⅲ restriction fragment patterns (characteristic of the paternal parent Cryptomeria fortunei ) and the trnL trnF region (identical to the maternal parent Cunninghamia lanceolata ) showing that a different mode of inheritance for organelle DNA has occurred in the hybrids. Furthermore, the maternal inheritance of chloroplast DNA is reported here for the first time in coniferophyta.

Eucaryotic DNA Methylation and Gene Mutation

5-methylcytosine (m5C) as a rare base exists in eucaryotic genomes, it is a normal constituent of many eucaryotic DNA, whose existence is a character of eucaryotic DNA. In the regular physiological conditions, cytosine residue of eucaryotic DNA is methylated to be popular. Up to the present, many people consider that the m5C may be mutation hotspots by the m5C deamination leading to gene mutation. Our theoretical investigations indicated that the spontaneous mutation caused by the transition of G - C-A - T, in eukaryotic DNA, may be a result caused by the tautomer changing base pairs and may also be caused by other factor actions, however it could not be caused by the deamination of m5C.