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EBioMedicine Feb 2022Mitochondrial DNA (mtDNA) encodes 37 genes necessary for synthesizing 13 essential subunits of the oxidative phosphorylation system. mtDNA alterations are known to cause...
BACKGROUND
Mitochondrial DNA (mtDNA) encodes 37 genes necessary for synthesizing 13 essential subunits of the oxidative phosphorylation system. mtDNA alterations are known to cause mitochondrial disease (MitD), a clinically heterogeneous group of disorders that often present with neuropsychiatric symptoms. Understanding the nature and frequency of mtDNA alterations in health and disease could be a cornerstone in disentangling the relationship between biochemical findings and clinical symptoms of brain disorders. This systematic review aimed to summarize the mtDNA alterations in human brain tissue reported to date that have implications for further research on the pathophysiological significance of mtDNA alterations in brain functioning.
METHODS
We searched the PubMed and Embase databases using distinct terms related to postmortem human brain and mtDNA up to June 10, 2021. Reports were eligible if they were empirical studies analysing mtDNA in postmortem human brains.
FINDINGS
A total of 158 of 637 studies fulfilled the inclusion criteria and were clustered into the following groups: MitD (48 entries), neurological diseases (NeuD, 55 entries), psychiatric diseases (PsyD, 15 entries), a miscellaneous group with controls and other clinical diseases (5 entries), ageing (20 entries), and technical issues (5 entries). Ten entries were ascribed to more than one group. Pathogenic single nucleotide variants (pSNVs), both homo- or heteroplasmic variants, have been widely reported in MitD, with heteroplasmy levels varying among brain regions; however, pSNVs are rarer in NeuD, PsyD and ageing. A lower mtDNA copy number (CN) in disease was described in most, but not all, of the identified studies. mtDNA deletions were identified in individuals in the four clinical categories and ageing. Notably, brain samples showed significantly more mtDNA deletions and at higher heteroplasmy percentages than blood samples, and several of the deletions present in the brain were not detected in the blood. Finally, mtDNA heteroplasmy, mtDNA CN and the deletion levels varied depending on the brain region studied.
INTERPRETATION
mtDNA alterations are well known to affect human tissues, including the brain. In general, we found that studies of MitD, NeuD, PsyD, and ageing were highly variable in terms of the type of disease or ageing process investigated, number of screened individuals, studied brain regions and technology used. In NeuD and PsyD, no particular type of mtDNA alteration could be unequivocally assigned to any specific disease or diagnostic group. However, the presence of mtDNA deletions and mtDNA CN variation imply a role for mtDNA in NeuD and PsyD. Heteroplasmy levels and threshold effects, affected brain regions, and mitotic segregation patterns of mtDNA alterations may be involved in the complex inheritance of NeuD and PsyD and in the ageing process. Therefore, more information is needed regarding the type of mtDNA alteration, the affected brain regions, the heteroplasmy levels, and their relationship with clinical phenotypes and the ageing process.
FUNDING
Hospital Universitari Institut Pere Mata; Institut d'Investigació Sanitària Pere Virgili; Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación (PI18/00514).
Topics: Brain; DNA, Mitochondrial; Humans; Mitochondria; Mitochondrial Diseases; Mutation
PubMed: 35085849
DOI: 10.1016/j.ebiom.2022.103815 -
Cell Journal May 2024The relationship between oxidative stress (OS), insulin resistance (IR), and polycystic ovary syndrome (PCOS) is an important medical issue in human reproduction. Some...
OBJECTIVE
The relationship between oxidative stress (OS), insulin resistance (IR), and polycystic ovary syndrome (PCOS) is an important medical issue in human reproduction. Some of the oxidative phosphorylation (OXPHOS) genes have been previously studied in granulosa and muscle cells of PCOS patients. Cumulus cells (CCs) remain close to the oocyte even after ovulation. This research has been designed to compare the expression of OXPHOS genes in CCs of PCOS, with or without insulin resistance.
MATERIALS AND METHODS
In this experimental study, patients were included in PCOS insulin-resistant, PCOS insulinsensitive (IS), and control (fertile women with male infertility history) groups. The expression of and was studied by real-time polymerase chain reaction (PCR), and normalization was performed considering and as reference genes. One-way ANOVA and Tukey test were used for data analysis.
RESULTS
The results showed that the expression of and was significantly higher in the IR group than IS and control groups (P<0.01). showed the highest expression in the IS group, which was significantly different from other groups (P<0.01). The other genes of interest, except , were observed with the most transcriptional levels in the IS group, although there was no significant difference for those genes.
CONCLUSION
Altered expression of genes involved in mitochondrial function compared to the control group in CCs of both IR and IS categories of the PCOS patients suggests that alteration in OXPHOS genes can contribute to the pathophysiology of PCOS.
PubMed: 38736407
DOI: 10.22074/cellj.2024.2006763.1357 -
Frontiers in Cardiovascular Medicine 2022The discovery that cardiac sarcomere proteins are substrates for S-glutathionylation and that this post-translational modification correlates strongly with diastolic...
The discovery that cardiac sarcomere proteins are substrates for S-glutathionylation and that this post-translational modification correlates strongly with diastolic dysfunction led to new concepts regarding how levels of oxidative stress affect the heartbeat. Major sarcomere proteins for which there is evidence of S-glutathionylation include cardiac myosin binding protein C (cMyBP-C), actin, cardiac troponin I (cTnI) and titin. Our hypothesis is that these S-glutathionylated proteins are significant factors in acquired and familial disorders of the heart; and, when released into the serum, provide novel biomarkers. We consider the molecular mechanisms for these effects in the context of recent revelations of how these proteins control cardiac dynamics in close collaboration with Ca fluxes. These revelations were made using powerful approaches and technologies that were focused on thin filaments, thick filaments, and titin filaments. Here we integrate their regulatory processes in the sarcomere as modulated mainly by neuro-humoral control of phosphorylation inasmuch evidence indicates that S-glutathionylation and protein phosphorylation, promoting increased dynamics and modifying the Frank-Starling relation, may be mutually exclusive. Earlier studies demonstrated that in addition to cTnI as a well-established biomarker for cardiac disorders, serum levels of cMyBP-C are also a biomarker for cardiac disorders. We describe recent studies approaching the question of whether serum levels of S-glutathionylated-cMyBP-C could be employed as an important clinical tool in patient stratification, early diagnosis in at risk patients before HFpEF, determination of progression, effectiveness of therapeutic approaches, and as a guide in developing future therapies.
PubMed: 36762302
DOI: 10.3389/fcvm.2022.1060716 -
Genome Research Apr 2024Mitochondrial DNA (mtDNA) variants cause a range of diseases from severe pediatric syndromes to aging-related conditions. The percentage of mtDNA copies carrying a...
Mitochondrial DNA (mtDNA) variants cause a range of diseases from severe pediatric syndromes to aging-related conditions. The percentage of mtDNA copies carrying a pathogenic variant, variant allele frequency (VAF), must reach a threshold before a biochemical defect occurs, termed the biochemical threshold. Whether the often-cited biochemical threshold of >60% VAF is similar across mtDNA variants and cell types is unclear. In our systematic review, we sought to identify the biochemical threshold of mtDNA variants in relation to VAF by human tissue/cell type. We used controlled vocabulary terms to identify articles measuring oxidative phosphorylation (OXPHOS) complex activities in relation to VAF. We identified 76 eligible publications, describing 69, 12, 16, and 49 cases for complexes I, III, IV, and V, respectively. Few studies evaluated OXPHOS activities in diverse tissue types, likely reflective of clinical access. A number of cases with similar VAFs for the same pathogenic variant had varying degrees of residual activity of the affected complex, alluding to the presence of modifying variants. Tissues and cells with VAFs <60% associated with low complex activities were described, suggesting the possibility of a biochemical threshold of <60%. Using Kendall rank correlation tests, the VAF of the m.8993T > G variant correlated with complex V activity in skeletal muscle (τ = -0.58, = 0.01, n = 13); however, no correlation was observed in fibroblasts ( = 0.7, n = 9). Our systematic review highlights the need to investigate the biochemical threshold over a wider range of VAFs in disease-relevant cell types to better define the biochemical threshold for specific mtDNA variants.
Topics: Humans; DNA, Mitochondrial; Gene Frequency; Genetic Variation; Mitochondria; Mitochondrial Diseases; Oxidative Phosphorylation
PubMed: 38627095
DOI: 10.1101/gr.278200.123 -
American Journal of Medical Genetics.... Jan 2023Biallelic pathogenic variants in the TARS2 gene cause combined oxidative phosphorylation deficiency, subtype 21 (COXPD21, MIM #615918), which is a rare mitochondrial...
Biallelic pathogenic variants in the TARS2 gene cause combined oxidative phosphorylation deficiency, subtype 21 (COXPD21, MIM #615918), which is a rare mitochondrial encephalomyopathy (ME) characterized by early-onset severe axial hypotonia, limb hypertonia, delayed psychomotor development, epilepsy, and brain anomalies. Currently, eight COXPD21 patients have been reported in the literature, and 11 pathogenic variants in TARS2 have been identified. Here, we report a 2-year-6-month-old Chinese female who presented with severe dystonia, developmental regression, absent speech, and intractable epilepsy. Laboratory examination showed persistently increased serum lactate. Brain MRI showed that the head of the caudate and partial lenticular nucleus were bilateral symmetrical T2-weighted imaging (T2WI) hyperintense and the corpus callosum was very thin. The clinical characteristics pointed to a ME. Trio-based whole-exome sequencing (WES) was employed to detect the causative variants. WES revealed novel compound heterozygous variants, c.470G>C (p.Thr157Arg) and c.2051C>T (p.Arg684Gln), in TARS2 in our patient that were inherited from the mother and father, respectively. Next, we systematically reviewed the available clinical features of COXPD21 patients and noticed that the reduced fetal movement observed in our patient may be a novel phenotype of COXPD21. These findings expand the mutation spectrum of TARS2 and provide insights into the genotype-phenotype relationship in COXPD21 as well as a foundation for its genetic counseling, diagnosis and treatment.
Topics: Humans; Female; Mitochondrial Encephalomyopathies; East Asian People; Exome Sequencing; Phenotype; Mutation
PubMed: 36218002
DOI: 10.1002/ajmg.a.62988 -
Frontiers in Oncology 2022This report analyzes nuclear receptor (NR) subfamily 4A's potential role in treating those diagnosed with breast cancer. Here we reviewed the current literature on NR4...
This report analyzes nuclear receptor (NR) subfamily 4A's potential role in treating those diagnosed with breast cancer. Here we reviewed the current literature on NR4 family members. We also examined the relative gene expression of the NR4A receptor subfamily in the basal, HER2 (human epidermal growth factor receptor 2) positive, luminal A, and luminal B subtypes using data from tumor samples in The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC). These data showed a positive link between NR4A1-NR4A3 expression and increased overall survival and relapse-free survival in breast cancer patients. In addition, we observed that high expression of NR4A1, NR4A2, and NR4A3 led to better survival. Furthermore, NR4A family genes seem to play an essential regulatory role in glycolysis and oxidative phosphorylation in breast cancer. The novel prognostic role of the NR4A1-NR4A3 receptors implicates these receptors as important mediators controlling breast cancer metabolic reprograming and its progression. The review establishes a strong clinical basis for the investigation of the cellular, molecular, and physiological roles of NR4A genes in breast cancer.
PubMed: 35547878
DOI: 10.3389/fonc.2022.777824 -
Genes Feb 2023Defect of , the human mitochondrial tRNA-modifying enzyme, can lead to Combined Oxidative Phosphorylation Deficiency 23 (COXPD23). Up to now, about 20 different variants...
Defect of , the human mitochondrial tRNA-modifying enzyme, can lead to Combined Oxidative Phosphorylation Deficiency 23 (COXPD23). Up to now, about 20 different variants of the gene have been reported; however, genotype-phenotype analysis has rarely been described. Here, we reported a 9-year-old boy with COXPD23 who presented with hyperlactatemia, hypertrophic cardiomyopathy, seizures, feeding difficulties, intellectual disability and motor developmental delay, and abnormal visual development. Biallelic pathogenic variants of the gene were identified in this boy, one novel variant c.1102dupC (p. Arg368Profs*22) inherited from the mother and the other known variant c.689A>C (p. Gln230Pro) inherited from father. We curated 18 COXPD23 patients with variants to investigate the genotype-phenotype correlation. We found that hyperlactatemia and cardiomyopathy were critical clinical features in COXPD23 and the average onset age was 1.7 years (3 months of age for the homozygote). Clinical classification of COXPD23 for the two types, severe and mild, was well described in this study. We observed arrhythmia and congestive heart failure frequently in the severe type with early childhood mortality, while developmental delay was mainly observed in the mild type. The proportion of homozygous variants (71.4%) significantly differed from that of compound heterozygous variants (18.1%) in the severe type. Compared with the variants in gnomAD, the proportion of LOFVs in was higher in COXPD23 patients (48.6% versus 8.9%, < 0.0001 ****), and 31% of them were frameshift variants, showing the LOF mechanism of . Additionally, the variants in patients were significantly enriched in the TrmE-type G domain, indicating that the G domain was crucial for protein function. The TrmE-type G domain contained several significant motifs involved in the binding of guanine nucleotides and Mg, the hydrolysis of GTP, and the regulation of the functional status of GTPases. In conclusion, we reported a mild COXPD23 case with typical -related symptoms, including seizures and abnormal visual development seldom observed previously. Our study provides novel insight into understanding the clinical diagnosis and genetic counseling of patients with COXPD23 by exploring the genetic pathogenesis and genotype-phenotype correlation of COXPD23.
Topics: Child; Child, Preschool; Humans; Infant; Male; GTP-Binding Proteins; Hyperlactatemia; Mitochondrial Diseases; Seizures
PubMed: 36980825
DOI: 10.3390/genes14030552 -
Frontiers in Physiology 2021Exposure to radiofrequency electromagnetic radiation (RF-EMR) from various wireless devices has increased dramatically with the advancement of technology. One of the...
Exposure to radiofrequency electromagnetic radiation (RF-EMR) from various wireless devices has increased dramatically with the advancement of technology. One of the most vulnerable organs to the RF-EMR is the testes. This is due to the fact that testicular tissues are more susceptible to oxidative stress due to a high rate of cell division and mitochondrial oxygen consumption. As a result of extensive cell proliferation, replication errors occur, resulting in DNA fragmentation in the sperm. While high oxygen consumption increases the level of oxidative phosphorylation by-products (free radicals) in the mitochondria. Furthermore, due to its inability to effectively dissipate excess heat, testes are also susceptible to thermal effects from RF-EMR exposure. As a result, people are concerned about its impact on male reproductive function. The aim of this article was to conduct a review of literature on the effects of RF-EMR emitted by wireless devices on male reproductive hormones in experimental animals and humans. According to the findings of the studies, RF-EMR emitted by mobile phones and Wi-Fi devices can cause testosterone reduction. However, the effect on gonadotrophic hormones (follicle-stimulating hormone and luteinizing hormone) is inconclusive. These findings were influenced by several factors, which can influence energy absorption and the biological effect of RF-EMR. The effect of RF-EMR in the majority of animal and human studies appeared to be related to the duration of mobile phone use. Thus, limiting the use of wireless devices is recommended.
PubMed: 34630149
DOI: 10.3389/fphys.2021.732420 -
Journal of Animal Science Jan 2024Improving the feeding efficiency of dairy cows is a key component to improve the utilization of land resources and meet the demand for high-quality protein. Advances in... (Meta-Analysis)
Meta-Analysis
Improving the feeding efficiency of dairy cows is a key component to improve the utilization of land resources and meet the demand for high-quality protein. Advances in genomic methods and omics techniques have made it possible to breed more efficient dairy cows through genomic selection. The aim of this review is to obtain a comprehensive understanding of the biological background of feed efficiency (FE) complex traits in purebred Holstein dairy cows including heritability estimate, and genetic markers, genes, and pathways participating in FE regulation mechanism. Through a literature search, we systematically reviewed the heritability estimation, molecular genetic markers, genes, biomarkers, and pathways of traits related to feeding efficiency in Holstein dairy cows. A meta-analysis based on a random-effects model was performed to combine reported heritability estimates of FE complex. The heritability of residual feed intake, dry matter intake, and energy balance was 0.20, 0.34, and 0.22, respectively, which proved that it was reasonable to include the related traits in the selection breeding program. For molecular genetic markers, a total of 13 single-nucleotide polymorphisms and copy number variance loci, associated genes, and functions were reported to be significant across populations. A total of 169 reported candidate genes were summarized on a large scale, using a higher threshold (adjusted P value < 0.05). Then, the subsequent pathway enrichment of these genes was performed. The important genes reported in the articles were included in a gene list and the gene list was enriched by gene ontology (GO):biological process (BP), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways analysis. Three GO:BP terms and four KEGG terms were statistically significant, which mainly focused on adenosine triphosphate (ATP) synthesis, electron transport chain, and OXPHOS pathway. Among these pathways, involved genes such as ATP5MC2, NDUFA, COX7A2, UQCR, and MMP are particularly important as they were previously reported. Twenty-nine reported biological mechanisms along with involved genes were explained mainly by four biological pathways (insulin-like growth factor axis, lipid metabolism, oxidative phosphorylation pathways, tryptophan metabolism). The information from this study will be useful for future studies of genomic selection breeding and genetic structures influencing animal FE. A better understanding of the underlying biological mechanisms would be beneficial, particularly as it might address genetic antagonism.
Topics: Female; Cattle; Animals; Lactation; Genetic Markers; Phenotype; Genome; Eating; Animal Feed; Milk
PubMed: 38354297
DOI: 10.1093/jas/skae040 -
Der Anaesthesist Jul 2020Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome is a rare progressive disease with acute neurological episodes caused by a... (Review)
Review
BACKGROUND
Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome is a rare progressive disease with acute neurological episodes caused by a mitochondriopathy. Due to a defect of oxidative phosphorylation in the respiratory chain, there is impaired mitochondrial energy production with subsequent lactic acidosis, especially in situations with increased stress. Due to the high risk of metabolic derailment MELAS syndrome is a great challenge with respect to the perioperative management of anesthesia.
OBJECTIVE
This article gives a general overview of the special features of anesthesia management in patients with MELAS syndrome. A case report is presented in order to demonstrate how intraoperative parenteral nutrition can possibly be used to counteract the formation of lactic acidosis.
MATERIAL AND METHODS
A systematic review of the literature was performed. As only very few reports on MELAS syndrome are available, a case report was also integrated into this overview article for illustration purposes.
RESULTS AND CONCLUSION
Patients with MELAS syndrome represent a challenging cohort with respect to management of anesthesia and an intensive monitoring of the metabolic status is crucial. In cases of increasing lactate values, the administration of intraoperative parenteral nutrition seems to be a suitable approach to avoid lactic acidosis and to improve the perioperative treatment of patients with MELAS syndrome in the future.
Topics: Adult; Anesthesia; Anesthesia, General; Anesthesiology; Female; Humans; Intraoperative Care; MELAS Syndrome
PubMed: 32424662
DOI: 10.1007/s00101-020-00793-8