Mitochondrial damage and related ocular disorders / 中华实验眼科杂志

Mitochondria are recognized to function as the powerhouse of the cell.The etiology of many common ocular disorders is increasingly recognized to involve either an accumulation of mitochondrial DNA (mtDNA) mutations and/or secondary mitochondrial damage.Novel pathogenic mtDNA mutations continue to be detected for primary mitochondrial ophthalmologic disorders that commonly affect the optic nerve,retina,and extraocular muscles.Mitochondrial dysfunction is also increasingly implicated in common ophthalmologic disorders,including diabetic retinopathy,age-related macular degeneration (AMD),and glaucoma.As the promise of personalized genomic medicine is becoming a reality,effective therapies for mitochondrial disorders are beginning to translate from bench to bedside along the paths of neuroprotection,gene replacement and stem cell-based regenerative paradigms.Additionally,preventing the transmission of pathogenic mtDNA mutations from mother to child is now a reality with in vitro fertilization mitochondrial replacement techniques.

Analysis of mitochondrial DNA mutation in leukemia / 肿瘤研究与临床

Objective To study the mitochondrial DNA mutation in leukemia.Methods Mitochondrial DNA of 16 leukemia patients in First Hospital of Qinhuangdao from February to June 2017 were amplified and sequenced by using polymerase chain reaction (PCR).The result was compared with revised Cambridge reference sequence (rCRS) and human mitochondrial genome database (mtDB),and the mutation was also analyzed.Results There were 106 mutation genes in total,including 47.17 ％ (50/106) in D-loop region,2.83 ％ (3/106) in ND4 region,17.92 ％ (19/106) in ND5 region,22.64 ％ (24/106) in Cytb region,7.55 ％ (8/106) in ND1 region,1.89 ％ (2/106) in Co Ⅱ region.Conclusion There is a high mitochondrial DNA mutation rate in leukemia patients.

Leigh Syndrome in Childhood: Neurologic Progression and Functional Outcome

BACKGROUND AND PURPOSE: Few studies have analyzed the clinical course and functional outcome in Leigh syndrome (LS). The aim of this study was to determine the clinical, radiological, biochemical, and genetic features of patients with LS, and identify prognostic indicators of the disease progression and neurological outcome. METHODS: Thirty-nine patients who had been diagnosed with LS at the Seoul National University Children's Hospital were included. Their medical records, neuroimaging findings, and histological/biochemical findings of skeletal muscle specimens were reviewed. Targeted sequencing of mitochondrial DNA was performed based on mitochondrial respiratory chain (MRC) enzyme defects. RESULTS: Isolated complex I deficiency was the most frequently observed MRC defect (in 42% of 38 investigated patients). Mitochondrial DNA mutations were identified in 11 patients, of which 81.8% were MT-ND genes. The clinical outcome varied widely, from independent daily activity to severe disability. Poor functional outcomes and neurological deterioration were significantly associated with early onset (before an age of 1 year) and the presence of other lesions additional to basal ganglia involvement in the initial neuroimaging. CONCLUSIONS: The neurological severity and outcome of LS may vary widely and be better than those predicted based on previous studies. We suggest that age at onset and initial neuroimaging findings are prognostic indicators in LS.

A peep into mitochondrial disorder: multifaceted from mitochondrial DNA mutations to nuclear gene modulation

Mitochondrial genome is responsible for multiple human diseases in a maternal inherited pattern, yet phenotypes of patients in a same pedigree frequently vary largely. Genes involving in epigenetic modification, RNA processing, and other biological pathways, rather than "threshold effect" and environmental factors, provide more specific explanation to the aberrant phenotype. Thus, the double hit theory, mutations both in mitochondrial DNA and modifying genes aggravating the symptom, throws new light on mitochondrial dysfunction processes. In addition, mitochondrial retrograde signaling pathway that leads to reconfiguration of cell metabolism to adapt defects in mitochondria may as well play an active role. Here we review selected examples of modifier genes and mitochondrial retrograde signaling in mitochondrial disorders, which refine our understanding and will guide the rational design of clinical therapies.

Mitochondrial molecular genetics for a pedigree with Leber hereditary optic neuropathy / 中华实验眼科杂志

Background Leber hereditary optic neuropathy (LHON)is a mitochondrial DNA (mtDNA)hereditary disease,so it is significant to understand the influence of DNA mutation on the occurrence of LHON.Objective This survey was to evaluate the role of mtDNA mutation in the development of LHON.Methods This survey study was approved by the Ethic Committee of Wuhan General Hospital of Guangzhou Military Command and written informed consent was obtained from each subject before the relative medial examination.Seventy-two matrilineal relatives from a family with LHON were collected for a pedigree analysis and mutation screening.Regular eye examination was performed on 11 patients,13 mutant gene carriers and 49 individuals with normal phenotype,and the degree of visual damage was graded as follows: ＞0.3 was normal,0.1-0.3 was mild damage,＜0.05-0.1 was moderate damage,＜0.02-0.05 was severe damage and ＜0.01 was very severe damage.Clinical characteristics of LHON was evaluated.The periphery blood sample of 2-4 ml was collected from individuals to separate the mononuclear cells,and the mtDNA was extracted by modified high salt method.MtDNA was amplified by PCR and the mutation loci was sequenced.Results PCR amplification product sequencing of mutant gene showed that both G11778A and T14502C mutations were detected in 24 of 72 matrilineal relatives,but only 11 of 24 carriers developed LHON.No abnormal clinical findings were seen in the 13 carriers,showing a less 50％ penetrance in this family.There was no G11778A or/and T14502C mutation in the normal phenotype individuals of this family.The onset age for vision impairment in 11 affected matrilineal relatives varied from 8 to 50 years old,with the mean age of 24.36 years old,showing a significantly lower age than that of the 13 carriers (5-72 years old,mean 40.38 years old) (t =2.102,P=0.049).Conclusions This study suggests that the Gl1778A and T14502C mutation in mitochondrial DNA is one of causes in the development of LHON.The primary G11778A mutation together with T14502C mutation in mtDNA is a factor for the occurrence of LHON,hut it is not sufficient to the development of LHON.An effective “second hit” process will play an inducing role for LHON.

Identifying potential pitfalls in interpreting mitochondrial DNA mutations of male infertility cases.

Background & objectives: Recently, a significantly higher ratio of nucleotide changes in the mtDNA genes: COII, ATPase 6, ATPase 8, ND2, ND3, ND4, and ND5 was reported in spermatozoa from populations of infertile Indian men, compared suggesting that screening for mtDNA mutations could provide insight into the aetiology of male infertility. In this study, we examined the published data and found serious errors in the original acquisition and analysis of the data. Methods: The mtDNA data associated with male infertility in Indian populations were retrieved from the published sources. The mtDNA substitution values of infertile and control groups were evaluated using phylogenetic methods and previously published mtDNA phylogenies. Results: Most of the mtDNA polymorphisms reported as significantly correlated with infertility were more commonly found in general populations. Further, our analysis showed that some of the mtDNA substitutions were erroneously overestimated in the infertile groups and underestimated in the control groups, and vice-versa. Interpretation & conclusions: Contrary to earlier claims, our analysis demonstrated no significant association between the mtDNA polymorphisms and male infertility in these studies. Further, these errors in the published data impune the usefulness of mitochondrial molecular analyses in male infertility diagnosis.

Clinical characteristics of diabetic pedigree with mtDNA 12026A→G mutation in Nd4 region / 中国糖尿病杂志

Objective To investigate clinical traits of 2 families members habouring mtDNA 12026A→G mutation based on our previous studies.Methods 25 members in 2 families with probands with mtDNA 12026 mutation were examined.All their clinical and biochemical data were collected.Total genome was extracted conventionally from peripheral leucocytes of all participants,and PCR-RFLP techniques were applied to screen A to G substitution at nucleotide 12026 of mtDNA in ND4 region.Results We found 13 individuals habouring the 12026 A→G mutation in 2 pedigrees,all without deafness.Among them,5 with diabetes were found.Interestingly,we found 3 individuals with hyperthyroidism in one family(one also combined with diabetes).Conclusions Our findings suggest that diabetic families with mtDNA 12026 A→G mutation in ND4 region can have different clinical pictures,and may involve in autoimmune diseases

Relationship between Mitochondrial DNA Point Mutation and Noise-induced Sensorineural Hearing Loss / 항공우주의학회지

BACKGROUND: A different sequence change in the mitochondrial 12S rRNA gene has been proposed as a candidate mutation in the sensorineural hearing loss. The purpose of this study was to study the association between the noise-induced sensorineural hearing loss and A to G mutation at nucleotide 1555 of mitochondrial DNA. METHODS: subjects were reviewed by history and medical records, and audiological and clinical data were obtained. Blood sampling was done on 101 normal controls, 51 with noise-induced sensorineural hearing loss, and 12 with sensorineurnal deafness. The DNA of these individuals were extracted, and mitochondrial genome were analyzed by polymerase chain reaction (PCR). Subsequently, the coding sequence of mitochondrial genome was sequenced and compared to the normal sequence, and all sequence variations were analyzed by restriction endonuclease BsmA I. RESULTS: Mitochondrial DNA mutant (1555A-->G) was not detected by PCR in all Korean patients with noise-induced hearing loss, sensorineural hearing loss, and in normal controls with no hearing loss. The DNA sequencing of PCR products did not reveal an A to G substitution at nucleotide 1,555 of mitochondrial DNA. CONCLUSION: This result suggests that the noise-induced sensorineural hearing loss is not associated with mitochondrial DNA mutation (1555A-->G).

MELAS Syndrome Presenting as Occipital Brain Infarct: Case Report / 대한뇌혈관외과학회지

MELAS syndrome is characterized by mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes. A 14-year-old male presented with symptoms that resemble stroke including headache, seizure, visual disturbance and slight left hemiparesis. Laboratory investigation showed elevated lactate level in the blood. Brain computed tomography and magnetic resonance image revealed acute infarction in the right occipitoparietal lobe, which was not restricted to a specific vascular territory. Magnetic resonance spectroscopy showed decreased N-acetyl aspartate and increased lactate level in the affected lobe. A molecular genetic analysis identified A3243G point mutation in the peripheral blood leukocytes and confirmed MELAS syndrome. We describe clinical, radiological and molecular genetic findings in the patient with MELAS syndrome presenting occipital brain infarct.

Clinical characteristics of diabetic pedigree with mtDNA 12026 A→G mutation in ND4 region / 中国糖尿病杂志

Objective To investigate clinical traits of 2 families members habouring mtDNA 12026A→G mutation based on our previous studies.Methods 25 members in 2 families with probands with mtDNA 12026 mutation were examined.All their clinical and biochemical data were collected.Total genome was extracted conventionally from peripheral leucocytes of all participants,and PCR-RFLP techniques were applied to screen A to G substitution at nucleotide 12026 of mtDNA in ND4 region.Results We found 13 individuals habouring the 12026 A→G mutation in 2 pedigrees,all without deafness.Among them,5 with diabetes were found.Interestingly,we found 3 individuals with hyperthyroidism in one family(one also combined with diabetes).Conclusions Our findings suggest that diabetic families with mtDNA 12026 A→G mutation in ND4 region can have different clinical pictures,and may involve in autoimmune diseases.

Mitochondrial DNA A3243G mutation in noise-induced sensorineural hearing loss / 대한산업의학회지

OBJECTIVES: A different sequence change, in the mitochondrial tRNA gene, has been proposed as a candidate mutation in the sensorineurnal hearing loss. The purpose of current study is to identify the association between the noise-induced sensorineurnal hearing loss and the A to G mutation at nucleotide 3243 of mitochondrial DNA. METHODS: Subjects were established by history and chart review, and audiological and clinical data were obtained. Blood was sampled from 101 controls, 50 noise-induced hearing loss, and 12 sensorineural deafness. The DNA of these individuals was extracted, and mitochondrial genome was analyzed by polymerase chain reaction. Subsequently, the coding sequence of mitochondrial genome was sequenced, and compared to the normal sequence, and all sequence variations were analyzed by restriction endonuclease ApaI. RESULTS: Mitochondrial DNA mutation (3243A->G) was not detected by polymerase chain reaction (PCR) in any patients with noise-induced hearing loss, sensorineural hearing loss, and normal control without hearing loss in Koreans. The DNA sequencing of PCR products did not revealed an A to G substitution at nucleotide 3243 of mitochondrial DNA. CONCLUSIONS: The noise-induced sensorineural hearing loss was not associated with mitochondrial DNA mutation (3243A->G)

MITOCHONDRIAL DNA MUTATION OF SPERMATOZOA OF INFERTILE MALE AND CHANGE OF MITOCHONDRIA-ULTRASTRUCTURE / 解剖学报

Objective To study the correlation of mitochondrial DNA mutation of spermatozoa and change of mitochondria-ultrastructure with male infertility. Methods The techniques of PCR and DNA sequence analysis were used to detect MTCYB and MTATP-6 fragments of 76 samples of semen with poor motility from infertile male.Of these samples five were identified with mitochondrial DNA deletion and transmission electron microscopic observations were made. Results Under the electron microscopic observations the 5 samples were all seen with abnormal volume of mitochondria in most spermatozoa tails either small or big, disorderly located and asymmetrically distributed;the axonemal structures of sperm wrapped in layers of mitochondria. These samples of sperm were noticeably different in form from those from fertile male. Conclusion Sperm mitochondria-ultrastructure change were observed in samples of sperm mitochondrial DNA mutation.Sperm mitochondrial mutation and its mitochondria-ultrastructure affect the energy supply of sperms during the process of fertilization which may result in male infertility.;