Genetic Alterations in Mitochondrial DNA Are Complementary to Nuclear DNA Mutations in Pheochromocytomas

Background: Somatic mutations, copy-number variations, and genome instability of mitochondrial DNA (mtDNA) have been reported in different types of cancers and are suggested to play important roles in cancer development and metastasis. However, there is scarce information about pheochromocytomas and paragangliomas (PCCs/PGLs) formation. Material: To determine the potential roles of mtDNA alterations in sporadic PCCs/PGLs, we analyzed a panel of 26 nuclear susceptibility genes and the entire mtDNA sequence of seventy-seven human tumors, using next-generation sequencing, and compared the results with normal adrenal medulla tissues. We also performed an analysis of copy-number alterations, large mtDNA deletion, and gene and protein expression. Results: Our results revealed that 53.2% of the tumors harbor a mutation in at least one of the targeted susceptibility genes, and 16.9% harbor complementary mitochondrial mutations. More than 50% of the mitochondrial mutations were novel and predicted pathogenic, affecting mitochondrial oxidative phosphorylation. Large deletions were found in 26% of tumors, and depletion of mtDNA occurred in more than 87% of PCCs/PGLs. The reduction of the mitochondrial number was accompanied by a reduced expression of the regulators that promote mitochondrial biogenesis (PCG1α, NRF1, and TFAM). Further, P62 and LC3a gene expression suggested increased mitophagy, which is linked to mitochondrial dysfunction. Conclusion: The pathogenic role of these finding remains to be shown, but we suggest a complementarity and a potential contributing role in PCCs/PGLs tumorigenesis.

The Mutations and Clinical Variability in Maternally Inherited Diabetes and Deafness: An Analysis of 161 Patients

AimsTo investigate the clinical features and mitochondrial mutations for maternally inherited diabetes and deafness.MethodsPubMed, Embase, Medline, Web of Science, the China National Knowledge Infrastructure, and Wanfang were searched with the following search terms: “Maternally inherited diabetes and deafness” OR “MIDD” OR “Mitochondrial diabetes”. The mutations and clinical features were analyzed. Correlation between the heteroplasmy levels of the m.3243A>G mutation in the peripheral blood and age at the onset of diabetes was conducted by Spearman test. The significance level was set as p < 0.05. Statistical analysis was performed using the Statistical Package for the Social Sciences version 26 for Windows.ResultsTotally 161 patients with 21 different mitochondrial mutations were enrolled. The most common mutation was the m.3243A>G mutation in 136 cases. Of 142 patients, 120 (84.51%) had family histories of diabetes or hearing loss. Hearing loss presented in 85.71% of the patients with mitochondrial mutations. Central nervous system diseases were found in 29.19%, myopathy in 22.98%, oculopathy in 23.60%, cardiac disease in 23.60%, and nephropathy in 13.66% of the patients. Forty-two of 101 (41.58%) patients were underweight. A significant negative correlation was found between the heteroplasmy levels of the m.3243A>G mutation in the peripheral blood and age at the onset of diabetes.ConclusionsThe young onset of diabetes with low or normal BMI, maternal inheritance, and presence of impairments of multiple systems should prompt a genetic testing in order to differentiate MIDD from other types of diabetes earlier.

Mitochondrial Mutations in Ethambutol-Induced Optic Neuropathy

Background: Ethambutol-induced optic neuropathy (EON) is a well-recognized ocular complication in patients who take ethambutol as a tuberculosis treatment. The aim of the current study was to investigate the presence of mitochondrial mutations, including OPA1 and Leber’s hereditary optic neuropathy (LHON)-mitochondrial DNA (mtDNA), in patients with EON and to determine their effect on clinical features of these patients.Methods: All 47 patients underwent clinical evaluations, including best-corrected visual acuity, fundus examination, and color fundus photography; 37 patients were then followed up over time. Molecular screening methods, including PCR-based sequencing of the OPA1 gene and LHON-mtDNA mutations, together with targeted exome sequencing, were used to detect mutations.Results: We detected 15 OPA1 mutations in 18 patients and two LHON-mtDNA mutations in four patients, for an overall mutation detection rate of 46.8%. The mean presentation age was significantly younger in the patients with the mitochondrial mutations (27.5 years) than in those without mutations (48 years). Fundus examination revealed a greater prevalence of optic disc hyperemia in the patients with mutations (70.5%) than without mutations (48%). Half of the patients with mutations and 91% of the patients without mutations had improved vision. After adjusting for confounders, the logistic regression revealed that the patients with optic disc pallor on the first visit (p = 0.004) or the patients with the mitochondrial mutations (p < 0.001) had a poorer vision prognosis.Conclusion: Our results indicated that carriers with OPA1 mutations might be more vulnerable for the toxicity of EMB to develop EON.

Human Mitochondrial DNA: Particularities and Diseases

Mitochondria are the cell’s power site, transforming energy into a form that the cell can employ for necessary metabolic reactions. These organelles present their own DNA. Although it codes for a small number of genes, mutations in mtDNA are common. Molecular genetics diagnosis allows the analysis of DNA in several areas such as infectiology, oncology, human genetics and personalized medicine. Knowing that the mitochondrial DNA is subject to several mutations which have a direct impact on the metabolism of the mitochondrion leading to many diseases, it is therefore necessary to detect these mutations in the patients involved. To date numerous mitochondrial mutations have been described in humans, permitting confirmation of clinical diagnosis, in addition to a better management of the patients. Therefore, different techniques are employed to study the presence or absence of mitochondrial mutations. However, new mutations are discovered, and to determine if they are the cause of disease, different functional mitochondrial studies are undertaken using transmitochondrial cybrid cells that are constructed by fusion of platelets of the patient that presents the mutation, with rho osteosarcoma cell line. Moreover, the contribution of next generation sequencing allows sequencing of the entire human genome within a single day and should be considered in the diagnosis of mitochondrial mutations.

The Role of Mitochondrial Genes in Neurodegenerative Disorders

: Mitochondrial disorders are clinically heterogeneous, resulting from nuclear gene and mitochondrial mutations that disturb the mitochondrial functions and dynamics. There is a lack of evidence linking mtDNA mutations to neurodegenerative disorders, mainly due to the absence of noticeable neuropathological lesions in postmortem samples. This review describes various gene mutations in Alzheimer's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis, Multiple Sclerosis, and Stroke. These abnormalities, including PINK1, Parkin, and SOD1 mutations, seem to reveal mitochondrial dysfunctions due to either mtDNA mutation or deletion, the mechanism of which remains unclear in depth.

Mitochondrial mutations in Caenorhabditis elegans show signatures of oxidative damage and an AT-bias

Rapid mutation rates are typical of mitochondrial genomes (mtDNAs) in animals, but it is not clear why. The difficulty of obtaining measurements of mtDNA mutation that are not biased by natural selection has stymied efforts to distinguish between competing hypotheses about the causes of high mtDNA mutation rates. Several studies which have measured mtDNA mutations in nematodes have yielded small datasets with conflicting conclusions about the relative abundance of different substitution classes (i.e. the mutation spectrum). We therefore leveraged Duplex Sequencing, a high-fidelity DNA sequencing technique, to characterize de novo mtDNA mutations in Caenorhabditis elegans. This approach detected nearly an order of magnitude more mtDNA mutations than documented in any previous nematode mutation study. Despite an existing extreme AT bias in the C. elegans mtDNA (75.6% AT), we found that a significant majority of mutations increase genomic AT content. Compared to some prior studies in nematodes and other animals, the mutation spectrum reported here contains an abundance of CG→AT transversions, supporting the hypothesis that oxidative damage may be a driver of mtDNA mutations in nematodes. Further, we found an excess of G→T and C→T changes on the coding DNA strand relative to the template strand, consistent with increased exposure to oxidative damage. Analysis of the distribution of mutations across the mtDNA revealed significant variation among protein-coding genes and as well as among neighboring nucleotides. This high-resolution view of mitochondrial mutations in C. elegans highlights the value of this system for understanding relationships among oxidative damage, replication error, and mtDNA mutation.