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1.
Orphanet J Rare Dis ; 19(1): 148, 2024 Apr 06.
Article in English | MEDLINE | ID: mdl-38582886

ABSTRACT

BACKGROUND: Most patients suffering from Leber hereditary optic neuropathy carry one of the three classic pathologic mutations, but not all individuals with these genetic alterations develop the disease. There are different risk factors that modify the penetrance of these mutations. The remaining patients carry one of a set of very rare genetic variants and, it appears that, some of the risk factors that modify the penetrance of the classical pathologic mutations may also affect the phenotype of these other rare mutations. RESULTS: We describe a large family including 95 maternally related individuals, showing 30 patients with Leber hereditary optic neuropathy. The mutation responsible for the phenotype is a novel transition, m.3734A > G, in the mitochondrial gene encoding the ND1 subunit of respiratory complex I. Molecular-genetic, biochemical and cellular studies corroborate the pathogenicity of this genetic change. CONCLUSIONS: With the study of this family, we confirm that, also for this very rare mutation, sex and age are important factors modifying penetrance. Moreover, this pedigree offers an excellent opportunity to search for other genetic or environmental factors that additionally contribute to modify penetrance.


Subject(s)
DNA, Mitochondrial , Optic Atrophy, Hereditary, Leber , Humans , DNA, Mitochondrial/genetics , Optic Atrophy, Hereditary, Leber/genetics , Pedigree , Mutation/genetics , Phenotype
2.
Int J Mol Sci ; 23(19)2022 Sep 20.
Article in English | MEDLINE | ID: mdl-36232299

ABSTRACT

Thymidine kinase (TK2) deficiency causes mitochondrial DNA depletion syndrome. We aimed to report the clinical, biochemical, genetic, histopathological, and ultrastructural features of a cohort of paediatric patients with TK2 deficiency. Mitochondrial DNA was isolated from muscle biopsies to assess depletions and deletions. The TK2 genes were sequenced using Sanger sequencing from genomic DNA. All muscle biopsies presented ragged red fibres (RRFs), and the prevalence was greater in younger ages, along with an increase in succinate dehydrogenase (SDH) activity and cytochrome c oxidase (COX)-negative fibres. An endomysial inflammatory infiltrate was observed in younger patients and was accompanied by an overexpression of major histocompatibility complex type I (MHC I). The immunofluorescence study for complex I and IV showed a greater number of fibres than those that were visualized by COX staining. In the ultrastructural analysis, we found three major types of mitochondrial alterations, consisting of concentrically arranged lamellar cristae, electrodense granules, and intramitochondrial vacuoles. The pathological features in the muscle showed substantial differences in the youngest patients when compared with those that had a later onset of the disease. Additional ultrastructural features are described in the muscle biopsy, such as sarcomeric de-structuration in the youngest patients with a more severe phenotype.


Subject(s)
Mitochondrial Myopathies , Thymidine Kinase/metabolism , DNA, Mitochondrial/analysis , DNA, Mitochondrial/genetics , Electron Transport Complex IV/genetics , Electron Transport Complex IV/metabolism , Humans , Mitochondrial Myopathies/genetics , Mitochondrial Myopathies/pathology , Muscle, Skeletal/metabolism , Myocardium/metabolism , Succinate Dehydrogenase , Thymidine Kinase/genetics
3.
Orphanet J Rare Dis ; 17(1): 316, 2022 08 19.
Article in English | MEDLINE | ID: mdl-35986281

ABSTRACT

Population frequency has been one of the most widely used criteria to help assign pathogenicity to newly described mitochondrial DNA variants. However, after sequencing this molecule in thousands of healthy individuals, it has been observed that a very large number of genetic variants have a very low population frequency, which has raised doubts about the utility of this criterion. By analyzing the genetic variation of mitochondrial DNA-encoded genes for oxidative phosphorylation subunits in 195,983 individuals from HelixMTdb that were not sequenced based on any medical phenotype, we show that rare variants are deleterious and, along with other criteria, population frequency is still a useful criterion to assign pathogenicity to newly described variants.


Subject(s)
DNA, Mitochondrial , Mitochondria , DNA, Mitochondrial/genetics , Mitochondria/genetics , Phenotype , Virulence
4.
Clin Genet ; 102(4): 339-344, 2022 10.
Article in English | MEDLINE | ID: mdl-35808913

ABSTRACT

Leber hereditary optic neuropathy is a mitochondrial disease mainly due to pathologic mutations in mitochondrial genes related to the respiratory complex I of the oxidative phosphorylation system. Genetic, physiological, and environmental factors modulate the penetrance of these mutations. We report two patients suffering from this disease and harboring a m.15950G > A mutation in the mitochondrial DNA-encoded gene for the threonine transfer RNA. We also provide evidences supporting the pathogenicity of this mutation.


Subject(s)
Optic Atrophy, Hereditary, Leber , DNA, Mitochondrial/genetics , Electron Transport Complex I/genetics , Humans , Mutation , Optic Atrophy, Hereditary, Leber/genetics , Optic Atrophy, Hereditary, Leber/pathology , RNA, Transfer/genetics
5.
Antioxidants (Basel) ; 11(4)2022 Apr 08.
Article in English | MEDLINE | ID: mdl-35453428

ABSTRACT

The quantification of mitochondrial respiratory chain (MRC) enzymatic activities is essential for diagnosis of a wide range of mitochondrial diseases, ranging from inherited defects to secondary dysfunctions. MRC lesion is frequently linked to extended cell damage through the generation of proton leak or oxidative stress, threatening organ viability and patient health. However, the intrinsic challenge of a methodological setup and the high variability in measuring MRC enzymatic activities represents a major obstacle for comparative analysis amongst institutions. To improve experimental and statistical robustness, seven Spanish centers with extensive experience in mitochondrial research and diagnosis joined to standardize common protocols for spectrophotometric MRC enzymatic measurements using minimum amounts of sample. Herein, we present the detailed protocols, reference ranges, tips and troubleshooting methods for experimental and analytical setups in different sample preparations and tissues that will allow an international standardization of common protocols for the diagnosis of MRC defects. Methodological standardization is a crucial step to obtain comparable reference ranges and international standards for laboratory assays to set the path for further diagnosis and research in the field of mitochondrial diseases.

6.
Dis Model Mech ; 15(3)2022 03 01.
Article in English | MEDLINE | ID: mdl-35191981

ABSTRACT

Pearson syndrome is a rare multisystem disease caused by single large-scale mitochondrial DNA deletions (SLSMDs). The syndrome presents early in infancy and is mainly characterised by refractory sideroblastic anaemia. Prognosis is poor and treatment is supportive, thus the development of new models for the study of Pearson syndrome and new therapy strategies is essential. In this work, we report three different cell models carrying an SLMSD: fibroblasts, transmitochondrial cybrids and induced pluripotent stem cells (iPSCs). All studied models exhibited an aberrant mitochondrial ultrastructure and defective oxidative phosphorylation system function, showing a decrease in different parameters, such as mitochondrial ATP, respiratory complex IV activity and quantity or oxygen consumption. Despite this, iPSCs harbouring 'common deletion' were able to differentiate into three germ layers. Additionally, cybrid clones only showed mitochondrial dysfunction when heteroplasmy level reached 70%. Some differences observed among models may depend on their metabolic profile; therefore, we consider that these three models are useful for the in vitro study of Pearson syndrome, as well as for testing new specific therapies. This article has an associated First Person interview with the first author of the paper.


Subject(s)
Lipid Metabolism, Inborn Errors , Mitochondrial Diseases , Congenital Bone Marrow Failure Syndromes/genetics , DNA, Mitochondrial/genetics , Humans , Lipid Metabolism, Inborn Errors/genetics , Mitochondrial Diseases/genetics , Muscular Diseases
7.
Mutat Res Rev Mutat Res ; 786: 108334, 2020.
Article in English | MEDLINE | ID: mdl-33339579

ABSTRACT

Dilated cardiomyopathy is a frequent and extremely heterogeneous medical condition. Deficits in the oxidative phosphorylation system have been described in patients suffering from dilated cardiomyopathy. Hence, mutations in proteins related to this biochemical pathway could be etiological factors for some of these patients. Here, we review the clinical phenotypes of patients harboring pathological mutations in genes related to the oxidative phosphorylation system, either encoded in the mitochondrial or in the nuclear genome, presenting with dilated cardiomyopathy. In addition to the clinical heterogeneity of these patients, the large genetic heterogeneity has contributed to an improper allocation of pathogenicity for many candidate mutations. We suggest criteria to avoid incorrect assignment of pathogenicity to newly found mutations and discuss possible therapies targeting the oxidative phosphorylation function.


Subject(s)
Cardiomyopathy, Dilated/genetics , Cardiomyopathy, Dilated/pathology , DNA, Mitochondrial/genetics , Humans , Mitochondria/genetics , Mitochondria/pathology , Mutation , Oxidative Phosphorylation , Phenotype
8.
Int J Mol Sci ; 21(9)2020 May 10.
Article in English | MEDLINE | ID: mdl-32397676

ABSTRACT

Mitochondrial oxidative phosphorylation disorders are extremely heterogeneous conditions. Their clinical and genetic variability makes the identification of reliable and specific biomarkers very challenging. Until now, only a few studies have focused on the effect of a defective oxidative phosphorylation functioning on the cell's secretome, although it could be a promising approach for the identification and pre-selection of potential circulating biomarkers for mitochondrial diseases. Here, we review the insights obtained from secretome studies with regard to oxidative phosphorylation dysfunction, and the biomarkers that appear, so far, to be promising to identify mitochondrial diseases. We propose two new biomarkers to be taken into account in future diagnostic trials.


Subject(s)
DNA, Mitochondrial/genetics , Fibroblast Growth Factors/metabolism , Growth Differentiation Factor 15/metabolism , Interleukin-6/metabolism , Mitochondrial Diseases/metabolism , Oxidative Phosphorylation , Vascular Endothelial Growth Factor A/metabolism , Biomarkers/metabolism , Fibroblast Growth Factors/genetics , Growth Differentiation Factor 15/genetics , Humans , Mitochondrial Diseases/genetics , Secretory Pathway/drug effects , Secretory Pathway/genetics , Vascular Endothelial Growth Factor A/genetics
9.
Clin Genet ; 97(5): 731-735, 2020 05.
Article in English | MEDLINE | ID: mdl-31912494

ABSTRACT

The frequency of dermatological manifestations in diseases due to mitochondrial DNA mutations is not well known, although multiple symmetric lipomatosis has been repeatedly associated to mitochondrial DNA mutations. Here, we present a patient suffering from multiple symmetric lipomatosis and other skin signs. We found a new mitochondrial DNA mutation, m.8357T>C, in the tRNALys -coding gene and, using a cybrid approach, confirmed its pathogenicity. A meta-analysis of the dermatological signs of the patient shows that they are not common in patients with confirmed mitochondrial DNA mutations and suggests that, in these cases, lipomatosis is not related to the oxidative phosphorylation dysfunction, but to an alteration of an additional function associated to particular mitochondrial tRNAs.


Subject(s)
DNA, Mitochondrial/genetics , Lipomatosis, Multiple Symmetrical/genetics , RNA, Transfer/genetics , Adult , Humans , Lipomatosis, Multiple Symmetrical/diagnostic imaging , Lipomatosis, Multiple Symmetrical/physiopathology , Male , Middle Aged , Mitochondria/genetics , Mitochondria/pathology , Mutation/genetics
10.
Orphanet J Rare Dis ; 14(1): 150, 2019 06 21.
Article in English | MEDLINE | ID: mdl-31226990

ABSTRACT

BACKGROUND: The vision loss in Leber hereditary optic neuropathy patients is due to mitochondrial DNA mutations. No treatment has shown a clear-cut benefit on a clinically meaningful end-point. However, clinical evidences suggest two therapeutic approaches: the reduction of the mutation load in heteroplasmic patients or the elevation of mitochondrial DNA amount in homoplasmic patients. RESULTS: Here we show that ketogenic treatment, in cybrid cell lines, reduces the percentage of the m.13094 T > C heteroplasmic mutation and also increases the mitochondrial DNA levels of the m.11778G > A mitochondrial genotype. CONCLUSIONS: These results suggest that ketogenic diet could be a therapeutic strategy for Leber hereditary optic neuropathy.


Subject(s)
DNA, Mitochondrial/genetics , Mutation/genetics , Optic Atrophy, Hereditary, Leber/genetics , Diet, Ketogenic , Female , Humans , Male , Point Mutation/genetics
11.
J Clin Med ; 8(1)2019 Jan 10.
Article in English | MEDLINE | ID: mdl-30634555

ABSTRACT

Mitochondrial diseases (MD) are a group of genetic and acquired disorders which present significant diagnostic challenges. Here we report the disease characteristics of a large cohort of pediatric MD patients (n = 95) with a definitive genetic diagnosis, giving special emphasis on clinical muscle involvement, biochemical and histopathological features. Of the whole cohort, 51 patients harbored mutations in nuclear DNA (nDNA) genes and 44 patients had mutations in mitochondrial DNA (mtDNA) genes. The nDNA patients were more likely to have a reduction in muscle fiber succinate dehydrogenase (SDH) stains and in SDH-positive blood vessels, while a higher frequency of mtDNA patients had ragged red (RRF) and blue fibers. The presence of positive histopathological features was associated with ophthalmoplegia, myopathic facies, weakness and exercise intolerance. In 17 patients younger than two years of age, RRF and blue fibers were observed only in one case, six cases presented cytochrome c oxidase (COX) reduction/COX-fibers, SDH reduction was observed in five and all except one presented SDH-positive blood vessels. In conclusion, muscle involvement was a frequent finding in our series of MD patients, especially in those harboring mutations in mtDNA genes.

12.
Enferm. infecc. microbiol. clín. (Ed. impr.) ; 36(9): 539-543, nov. 2018. tab, graf
Article in English | IBECS | ID: ibc-176829

ABSTRACT

OBJECTIVE: The comparison on mitochondrial function between severe septic patients and healthy control subjects according to mitochondrial deoxyribonucleic acid (mtDNA) haplogroup has not been previously reported; and this was the objective of the current study. METHODS: Prospective, multicenter, observational study. We obtained blood samples from 198 severe septic patients at days 1, 4 and 8 of severe sepsis diagnosis and from 96 sex- and age-matched healthy controls to determine mtDNA haplogroup and platelet respiratory complex IV (CIV) specific activity. The endpoint of the study was 30-day mortality. RESULTS: We included 198 severe septic patients (38 with mtDNA haplogroup JT and 160 with mtDNA haplogroup non-JT) and 96 healthy control subjects (16 with mtDNA haplogroup JT and 80 with mtDNA haplogroup non-JT). We have no found statistically significant differences in platelet CIV specific activity between healthy controls and survivor severe septic patients with mtDNA haplogroup JT at days 1, 4 and 8 of severe sepsis diagnosis; and the remaining severe septic patients showed lower platelet CIV specific activity than healthy controls with the same mtDNA haplogroup. CONCLUSIONS: The new finding of our study was that survivor severe septic patients and healthy controls with mtDNA haplogroup JT showed no different platelet Civ specific activity


OBJETIVO: La comparación en la función mitocondrial entre pacientes con sepsis grave y sujetos sanos según el haplogrupo del ácido desoxirribonucleico mitocondrial (ADNmt) no se ha reportado previamente; y este fue el objetivo del estudio. MÉTODOS: Estudio prospectivo, multicéntrico y observacional. Obtuvimos muestras sanguíneas de 198 pacientes con sepsis grave en los días 1, 4 y 8 del diagnóstico de la sepsis grave y de 96 sujetos sanos para determinar el haplogrupo del ADNmt y la actividad del complejo respiratorio mitocondrial IV (CIV) en plaquetas circulantes. La variable resultado principal del estudio fue la mortalidad a los 30 días. RESULTADOS: Se incluyeron 198 pacientes con sepsis grave (38 con haplogrupo JT del ADNmt y 160 con otro haplogrupo del ADNmt) y 96 sujetos sanos (16 con haplogrupo JT del ADNmt y 80 con otro haplogrupo del ADNmt). No encontramos diferencias estadísticamente significativas en la actividad de CIV plaquetaria entre los sujetos sanos y los pacientes sépticos supervivientes con haplogrupo JT del ADNmt en los días 1, 4 y 8 del diagnóstico de la sepsis grave; y el resto de los pacientes sépticos presentaron menor actividad de CIV plaquetaria que los sujetos sanos con su mismo haplogrupo del ADNmt. CONCLUSIONES: El nuevo hallazgo de nuestro estudio fue que los pacientes sépticos y sujetos sanos con haplogrupo JT del ADNmt no tenían diferencias en la actividad de CIV plaquetaria


Subject(s)
Humans , Male , Female , Middle Aged , Aged , Mitochondria/genetics , Mitochondria/metabolism , Sepsis/blood , Sepsis/physiopathology , Blood Platelets , Prospective Studies , Case-Control Studies , Sepsis/mortality , Spain/epidemiology , Intensive Care Units
13.
J Clin Med ; 7(8)2018 Aug 16.
Article in English | MEDLINE | ID: mdl-30115863

ABSTRACT

The association between mitochondrial DNA (mtDNA) haplogroup and risk of type 2 diabetes (T2D) is undetermined and controversial. This study aims to evaluate the impact of the main mtDNA haplogroups on glycaemic control and renal function in a Spanish population of 303 T2D patients and 153 healthy controls. Anthropometrical and metabolic parameters were assessed and mtDNA haplogroup was determined in each individual. Distribution of the different haplogroups was similar in diabetic and healthy populations and, as expected, T2D patients showed poorer glycaemic control and renal function than controls. T2D patients belonging to the JT haplogroup (polymorphism m.4216T>C) displayed statistically significant higher levels of fasting glucose and HbA1c than those of the other haplogroups, suggesting a poorer glycaemic control. Furthermore, diabetic patients with the JT haplogroup showed a worse kidney function than those with other haplogroups, evident by higher levels of serum creatinine, lower estimated glomerular filtration rate (eGFR), and slightly higher (although not statistically significant) urinary albumin-to-creatinine ratio. Our results suggest that JT haplogroup (in particular, change at position 4216 of the mtDNA) is associated with poorer glycaemic control in T2D, which can trigger the development of diabetic nephropathy.

14.
Food Chem Toxicol ; 120: 89-97, 2018 Oct.
Article in English | MEDLINE | ID: mdl-29991444

ABSTRACT

Mitochondrial DNA mutations in genes encoding respiratory complex I polypeptides can cause Leber hereditary optic neuropathy. Toxics affecting oxidative phosphorylation system can also cause mitochondrial optic neuropathy. Some complex I inhibitors found in edible plants might differentially interact with these pathologic mutations and modify their penetrance. To analyze this interaction, we have compared the effect of rotenone, capsaicin and rolliniastatin-1 on cybrids harboring the most frequent Leber hereditary optic neuropathy mutations and found that m.3460G > A mutation increases rotenone resistance but capsaicin and rolliniastatin-1 susceptibility. Thus, to explain the pathogenicity of mitochondrial diseases due to mitochondrial DNA mutations, their potential interactions with environment factors will have to be considered.


Subject(s)
Electron Transport Complex I/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Food Analysis , Optic Atrophy, Hereditary, Leber/genetics , Point Mutation , Xenobiotics/toxicity , Apoptosis/drug effects , Capsaicin/pharmacology , Cell Line , DNA, Mitochondrial/genetics , Electron Transport Complex I/metabolism , Furans/pharmacology , Gene-Environment Interaction , Humans , Oxidative Phosphorylation , Oxygen Consumption/drug effects , Rotenone/pharmacology
15.
Front Neurosci ; 12: 61, 2018.
Article in English | MEDLINE | ID: mdl-29479304

ABSTRACT

The onset of Leber hereditary optic neuropathy is relatively rare in childhood and, interestingly, the rate of spontaneous visual recovery is very high in this group of patients. Here, we report a child harboring a rare pathological mitochondrial DNA mutation, present in heteroplasmy, associated with the disease. A patient follow-up showed a rapid recovery of the vision accompanied by a decrease of the percentage of mutated mtDNA. A retrospective study on the age of recovery of all childhood-onset Leber hereditary optic neuropathy patients reported in the literature suggested that this process was probably related with pubertal changes.

16.
Drug Discov Today ; 23(3): 493-498, 2018 03.
Article in English | MEDLINE | ID: mdl-29337205

ABSTRACT

Leber hereditary optic neuropathy (LHON) is a rare, inherited mitochondrial disease. No treatment has shown a clear-cut benefit on a clinically meaningful end-point. Primary open-angle glaucoma (POAG) is a frequent, acquired optic neuropathy. Lowering intraocular pressure (IOP) reduces disease progression. However, current methods to decelerate this progression are recognized as being inadequate. Therefore, there is a clear need to look for new therapeutic approaches. The growing evidence indicates that POAG can also be a mitochondrial optic neuropathy (MON). Several risk elements are common for both diseases and all of them decrease mitochondrial (mt)DNA content. Based on these susceptibility factors and their molecular mechanism, we suggest herein pharmacological therapies targeted to increase mtDNA levels, oxidative phosphorylation (OXPHOS) capability, and mitochondrial energy production as treatments for MONs.


Subject(s)
DNA, Mitochondrial/genetics , Mitochondria/genetics , Mitochondrial Diseases/genetics , Optic Atrophy, Hereditary, Leber/genetics , Animals , Glaucoma, Open-Angle/genetics , Humans , Oxidative Phosphorylation
17.
Enferm Infecc Microbiol Clin (Engl Ed) ; 36(9): 539-543, 2018 Nov.
Article in English, Spanish | MEDLINE | ID: mdl-29054538

ABSTRACT

OBJECTIVE: The comparison on mitochondrial function between severe septic patients and healthy control subjects according to mitochondrial deoxyribonucleic acid (mtDNA) haplogroup has not been previously reported; and this was the objective of the current study. METHODS: Prospective, multicenter, observational study. We obtained blood samples from 198 severe septic patients at days 1, 4 and 8 of severe sepsis diagnosis and from 96 sex- and age-matched healthy controls to determine mtDNA haplogroup and platelet respiratory complex IV (CIV) specific activity. The endpoint of the study was 30-day mortality. RESULTS: We included 198 severe septic patients (38 with mtDNA haplogroup JT and 160 with mtDNA haplogroup non-JT) and 96 healthy control subjects (16 with mtDNA haplogroup JT and 80 with mtDNA haplogroup non-JT). We have no found statistically significant differences in platelet CIV specific activity between healthy controls and survivor severe septic patients with mtDNA haplogroup JT at days 1, 4 and 8 of severe sepsis diagnosis; and the remaining severe septic patients showed lower platelet CIV specific activity than healthy controls with the same mtDNA haplogroup. CONCLUSIONS: The new finding of our study was that survivor severe septic patients and healthy controls with mtDNA haplogroup JT showed no different platelet Civ specific activity.


Subject(s)
DNA, Mitochondrial/genetics , Haplotypes , Mitochondria/physiology , Sepsis/physiopathology , Adult , Aged , DNA, Mitochondrial/blood , DNA, Mitochondrial/classification , Electron Transport Complex IV/blood , Electron Transport Complex IV/genetics , Female , Genetic Predisposition to Disease , Humans , Male , Middle Aged , Oxidative Phosphorylation , Prognosis , Prospective Studies , Sepsis/blood , Sepsis/genetics , Sepsis/mortality , Survivors
18.
Redox Biol ; 13: 244-254, 2017 10.
Article in English | MEDLINE | ID: mdl-28600981

ABSTRACT

The oxidative phosphorylation system is important for adipocyte differentiation. Therefore, xenobiotics inhibitors of the oxidative phosphorylation system could affect adipocyte differentiation and adipokine secretion. As adipokines impact the overall health status, these xenobiotics may have wide effects on human health. Some of these xenobiotics are widely used therapeutic drugs, such as ribosomal antibiotics. Because of its similarity to the bacterial one, mitochondrial translation system is an off-target for these compounds. To study the influence of the ribosomal antibiotic linezolid on adipokine production, we analyzed its effects on adipocyte secretome. Linezolid, at therapeutic concentrations, modifies the levels of apolipoprotein E and several adipokines and proteins related with the extracellular matrix. This antibiotic also alters the global methylation status of human adipose tissue-derived stem cells and, therefore, its effects are not limited to the exposure period. Besides their consequences on other tissues, xenobiotics acting on the adipocyte oxidative phosphorylation system alter apolipoprotein E and adipokine production, secondarily contributing to their systemic effects.


Subject(s)
Adipocytes/drug effects , Adipokines/metabolism , Linezolid/pharmacology , Oxidative Phosphorylation , Protein Synthesis Inhibitors/pharmacology , Adipocytes/metabolism , Cells, Cultured , Exocytosis , Humans
19.
Eur J Hum Genet ; 25(1): 153-156, 2016 01.
Article in English | MEDLINE | ID: mdl-27677415

ABSTRACT

Oxidative phosphorylation dysfunction has been found in many different disorders. This biochemical pathway depends on mitochondrial protein synthesis. Thus, mutations in components of the mitochondrial translation system can be responsible for some of these pathologies. We identified a new homozygous missense mutation in the mitochondrial translation elongation factor Ts gene in a patient suffering from slowly progressive childhood ataxia and hypertrophic cardiomyopathy. Using cell, biochemical and molecular-genetic protocols, we confirm it as the etiologic factor of this phenotype. Moreover, as an important functional confirmation, we rescued the normal molecular phenotype by expression of the wild-type TSFM cDNA in patient's fibroblasts. Different TSFM mutations can produce the same or very different clinical phenotypes, going from abortions to moderately severe presentations. On the other hand, the same TSFM mutation can also produce same or different phenotypes within the same range of presentations, therefore suggesting the involvement of unknown factors.


Subject(s)
Ataxia/genetics , Cardiomyopathies/genetics , Mitochondria/genetics , Mitochondrial Proteins/genetics , Oxidative Phosphorylation , Peptide Chain Elongation, Translational/genetics , Peptide Elongation Factors/genetics , Adult , Amino Acid Sequence , Ataxia/pathology , Biopsy , Cardiomyopathies/pathology , DNA, Mitochondrial/genetics , Fibroblasts , Gene Expression Regulation , Homozygote , Humans , Male , Mitochondria/pathology , Muscles/metabolism , Muscles/pathology , Mutation , Pedigree , Phenotype , Young Adult
20.
Mitochondrion ; 30: 51-8, 2016 09.
Article in English | MEDLINE | ID: mdl-27374853

ABSTRACT

We evaluated the coenzyme Q10 (CoQ) levels in patients who were diagnosed with mitochondrial oxidative phosphorylation (OXPHOS) and non-OXPHOS disorders (n=72). Data from the 72 cases in this study revealed that 44.4% of patients showed low CoQ concentrations in either their skeletal muscle or skin fibroblasts. Our findings suggest that secondary CoQ deficiency is a common finding in OXPHOS and non-OXPHOS disorders. We hypothesize that cases of CoQ deficiency associated with OXPHOS defects could be an adaptive mechanism to maintain a balanced OXPHOS, although the mechanisms explaining these deficiencies and the pathophysiological role of secondary CoQ deficiency deserves further investigation.


Subject(s)
Mitochondrial Diseases/pathology , Oxidative Phosphorylation , Ubiquinone/analogs & derivatives , Adolescent , Adult , Child , Child, Preschool , Cohort Studies , Female , Humans , Infant , Infant, Newborn , Male , Middle Aged , Muscles/pathology , Prevalence , Skin/pathology , Ubiquinone/deficiency , Young Adult
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