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1.
Int J Mol Sci ; 21(9)2020 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-32397676

RESUMO

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.

2.
Curr Biol ; 30(6): 1119-1127.e5, 2020 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-32142709

RESUMO

In mitochondria, the carrier translocase (TIM22 complex) facilitates membrane insertion of multi-spanning proteins with internal targeting signals into the inner membrane [1-3]. Tom70, a subunit of TOM complex, represents the major receptor for these precursors [2, 4-6]. After transport across the outer membrane, the hydrophobic carriers engage with the small TIM protein complex composed of Tim9 and Tim10 for transport across the intermembrane space (IMS) toward the TIM22 complex [7-12]. Tim22 represents the pore-forming core unit of the complex [13, 14]. Only a small subset of TIM22 cargo molecules, containing four or six transmembrane spans, have been experimentally defined. Here, we used a tim22 temperature-conditional mutant to define the TIM22 substrate spectrum. Along with carrier-like cargo proteins, we identified subunits of the mitochondrial pyruvate carrier (MPC) as unconventional TIM22 cargos. MPC proteins represent substrates with atypical topology for this transport pathway. In agreement with this, a patient affected in TIM22 function displays reduced MPC levels. Our findings broaden the repertoire of carrier pathway substrates and challenge current concepts of TIM22-mediated transport processes.

3.
Clin Genet ; 97(5): 731-735, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31912494

RESUMO

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.

4.
Neurogenetics ; 21(1): 19-27, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31655921

RESUMO

A 3-year-old girl presented with severe epilepsy in the context of Borrelia infection. After ceftriaxone/lidocaine administration, she showed secondarily generalized focal crises that led to neurological and motor sequelae. Genetic studies identified in the patient two heterozygous POLG mutations (c.2591A>G; p.Asn864Ser and c.3649G>C; p.Ala1217Pro). Through analysis of POLG activity in cultured fibroblasts, we confirmed that the mutations altered the mtDNA turnover. Moreover, patient fibroblasts were more sensitive than controls in the presence of a mitochondrial replication-affecting drug, the antiretroviral azidothymidine. To test if ceftriaxone treatment could worsen the deleterious effect of the patient mutations, toxicity assays were performed. Cell toxicity, without direct effect on mitochondrial respiratory function, was detected at different antibiotic concentrations. The clinical outcome, together with the different in vitro sensitivity to ceftriaxone among patient and control cells, suggested that the mitochondrial disease symptoms were hastened by the infection and were possibly worsened by the pharmacological treatment. This study underscores the benefit of early genetic diagnosis of the patients with mitochondrial diseases, since they may be a target group of patients especially vulnerable to environmental factors.

5.
Mitochondrion ; 50: 14-18, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31639449

RESUMO

We report the case of two members of the same family with a novel mitochondrial DNA (mtDNA) gene variant in the MT-ND5 gene associated with MELAS syndrome and discuss limitations of genetics studies. The m.13045A > G mutation was detected at very low load in the daughter's urine cells (5%) and at different levels in the skeletal muscle of both mother (50%) and daughter (84%), being absent in blood, hair and saliva. Our findings suggest that non-invasive genetic assessment in urine cells may not be a sensitive diagnostic method neither a good predictor of disease development in relatives of some families with mtDNA-associated MELAS, particularly if involving MT-ND5 gene.

6.
J Pediatr Genet ; 8(4): 231-234, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31687263

RESUMO

This article reports a Leber hereditary optic neuropathy (LHON) case associated for the first time with mitochondrial m.13513G>A mutation. We present a 16-year-old man who complained of subacute, painless, visual loss. Ocular examination showed optic nerve atrophy, papillary pseudoedema, and optic disc pallor. Extraocular manifestations included hypertrophic myocardiopathy and myopathy. Initial genetic analysis excluded the three most common LHON mutations. Sanger sequencing of the whole mitochondrial deoxyribonucleic acid showed no mutation. Next-generation sequencing (NGS) revealed m.13513G>A mutation in the NADH dehydrogenase (ND5) subunit gene ( MT-ND5 ). The m.13513G>A mutation has never been associated with LHON phenotype without Leigh/mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes features. NGS techniques should be considered when this diagnosis is strongly suspected.

7.
Cells ; 8(11)2019 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-31717322

RESUMO

Neuronal differentiation appears to be dependent on oxidative phosphorylation capacity. Several drugs inhibit oxidative phosphorylation and might be detrimental for neuronal differentiation. Some pregnant women take these medications during their first weeks of gestation when fetal nervous system is being developed. These treatments might have later negative consequences on the offspring's health. To analyze a potential negative effect of three widely used medications, we studied in vitro dopaminergic neuronal differentiation of cells exposed to pharmacologic concentrations of azidothymidine for acquired immune deficiency syndrome; linezolid for multidrug-resistant tuberculosis; and atovaquone for malaria. We also analyzed the dopaminergic neuronal differentiation in brains of fetuses from pregnant mice exposed to linezolid. The drugs reduced the in vitro oxidative phosphorylation capacity and dopaminergic neuronal differentiation. This differentiation process does not appear to be affected in the prenatally exposed fetus brain. Nevertheless, the global DNA methylation in fetal brain was significantly altered, perhaps linking an early exposure to a negative effect in older life. Uridine was able to prevent the negative effects on in vitro dopaminergic neuronal differentiation and on in vivo global DNA methylation. Uridine could be used as a protective agent against oxidative phosphorylation-inhibiting pharmaceuticals provided during pregnancy when dopaminergic neuronal differentiation is taking place.

8.
Aging (Albany NY) ; 11(19): 8433-8462, 2019 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-31560653

RESUMO

Many patients suffering late-onset Alzheimer disease show a deficit in respiratory complex IV activity. The de novo pyrimidine biosynthesis pathway connects with the mitochondrial respiratory chain upstream from respiratory complex IV. We hypothesized that these patients would have decreased pyrimidine nucleotide levels. Then, different cell processes for which these compounds are essential, such as neuronal membrane generation and maintenance and synapses production, would be compromised. Using a cell model, we show that inhibiting oxidative phosphorylation function reduces neuronal differentiation. Linking these processes to pyrimidine nucleotides, uridine treatment recovers neuronal differentiation. To unmask the importance of these pathways in Alzheimer disease, we firstly confirm the existence of the de novo pyrimidine biosynthesis pathway in adult human brain. Then, we report altered mRNA levels for genes from both de novo pyrimidine biosynthesis and pyrimidine salvage pathways in brain from patients with Alzheimer disease. Thus, uridine supplementation might be used as a therapy for those Alzheimer disease patients with low respiratory complex IV activity.

9.
Orphanet J Rare Dis ; 14(1): 150, 2019 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-31226990

RESUMO

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.

10.
Animals (Basel) ; 9(6)2019 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-31212935

RESUMO

Sexual dimorphism in the Laysan albatross (Phoebastria immutabilis) on Guadalupe Island was evaluated during the breeding seasons of 2015-2018 by measuring and comparing 10 morphological attributes: cranial length, bill length, nostril length, cranial width, bill height, bill width, tarsus length, closed wing length, opened wing length, and wingspan length in reproductive adults (n = 135). Males were larger than females across all traits (Student's t-test, p < 0.05, p < 0.05). We created a logistic model using stepwise regression to predict sex based on morphological variables. This model indicated four significant morphological predictor variables (z < 0.05) and was able to successfully predict the sex of P. immutabilis individuals in more than 90% of the cases. Based on these predictor variables, a web app was developed to determine the sex of the Laysan albatross in the field, providing a non-invasive method for rapid data collection that reduces costs and handling times while improving conservation efforts. We tracked Laysan albatross (n = 36) during breeding seasons and found no significant differences between females and males for either trip length (GLMM, F = 0.017, DF = 1, 1, p = 0.917 > 0.05) or maximum trip distance (GLMM, F = 0.374, DF = 1, 1, p = 0.651 > 0.05). Our results suggest that both sexes show a strong preference to travel to highly productive coastal waters northeast of the breeding colony that are influenced by the California Current. The present research will serve to establish a baseline to protect this species on Guadalupe Island and highlights the importance of understanding sexual dimorphism in at-risk seabird species.

11.
Drug Discov Today ; 24(9): 1731-1734, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30880173

RESUMO

Pathological mutations in subunits of the oxidative phosphorylation (OXPHOS) system, or inhibitors of this biochemical pathway, increase the production of vascular endothelial growth factor (VEGF) and pathological angiogenesis. In many angiogenesis-related diseases, such as retinal, rheumatoid diseases, or cancer, OXPHOS dysfunction can be found. Thus, enhancing OXPHOS might be a promising therapeutic approach for pathologic angiogenesis.

12.
J Clin Med ; 8(1)2019 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-30634555

RESUMO

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.

13.
Mol Genet Metab ; 126(3): 250-258, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30642748

RESUMO

AIM: To perform a deep phenotype characterisation in a pedigree of 3 siblings with Leigh syndrome and compound heterozygous NDUFAF6 mutations. METHOD: A multi-gene panel of childhood-onset basal ganglia neurodegeneration inherited conditions was analysed followed by functional studies in fibroblasts. RESULTS: Three siblings developed gait dystonia in infancy followed by rapid progression to generalised dystonia and psychomotor regression. Brain magnetic resonance showed symmetric and bilateral cytotoxic lesions in the putamen and proliferation of the lenticular-striate arteries, latter spreading to the caudate and progressing to cavitation and volume loss. We identified a frameshift novel change (c.554_558delTTCTT; p.Tyr187AsnfsTer65) and a pathogenic missense change (c.371T>C; p.Ile124Thr) in the NDUFAF6 gene, which segregated with an autosomal recessive inheritance within the family. Patient mutations were associated with the absence of the NDUFAF6 protein and reduced activity and assembly of mature complex I in fibroblasts. By functional complementation assay, the mutant phenotype was rescued by the canonical version of the NDUFAF6. A literature review of 14 NDUFAF6 patients showed a consistent phenotype of an early childhood insidious onset neurological regression with prominent dystonia associated with basal ganglia degeneration and long survival. INTERPRETATION: NDUFAF6-related Leigh syndrome is a relevant cause of childhood onset dystonia and isolated bilateral striatal necrosis. By genetic complementation, we could demonstrate the pathogenicity of novel genetic variants in NDUFAF6.


Assuntos
Distúrbios Distônicos/genética , Complexo I de Transporte de Elétrons/genética , Doença de Leigh/genética , Proteínas Mitocondriais/genética , Degeneração Estriatonigral/congênito , Biópsia , Criança , Estudos de Coortes , Feminino , Fibroblastos , Expressão Gênica , Variação Genética , Humanos , Doença de Leigh/complicações , Masculino , Músculos/patologia , Mutação , Linhagem , Irmãos , Degeneração Estriatonigral/genética
14.
Sci Rep ; 9(1): 793, 2019 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-30692599

RESUMO

Identifying diseases displaying chronic low plasma Coenzyme Q10 (CoQ) values may be important to prevent possible cardiovascular dysfunction. The aim of this study was to retrospectively evaluate plasma CoQ concentrations in a large cohort of pediatric and young adult patients. We evaluated plasma CoQ values in 597 individuals (age range 1 month to 43 years, average 11 years), studied during the period 2005-2016. Patients were classified into 6 different groups: control group of healthy participants, phenylketonuric patients (PKU), patients with mucopolysaccharidoses (MPS), patients with other inborn errors of metabolism (IEM), patients with neurogenetic diseases, and individuals with neurological diseases with no genetic diagnosis. Plasma total CoQ was measured by reverse-phase high-performance liquid chromatography with electrochemical detection and ultraviolet detection at 275 nm. ANOVA with Bonferroni correction showed that plasma CoQ values were significantly lower in the PKU and MPS groups than in controls and neurological patients. The IEM group showed intermediate values that were not significantly different from those of the controls. In PKU patients, the Chi-Square test showed a significant association between having low plasma CoQ values and being classic PKU patients. The percentage of neurogenetic and other neurological patients with low CoQ values was low (below 8%). In conclusión, plasma CoQ monitoring in selected groups of patients with different IEM (especially in PKU and MPS patients, but also in IEM under protein-restricted diets) seems advisable to prevent the possibility of a chronic blood CoQ suboptimal status in such groups of patients.

15.
Gene ; 688: 171-181, 2019 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-30528267

RESUMO

Mitochondria both produce the energy of the cell as ATP via respiration and regulate cellular metabolism. Accordingly, any deletion or mutation in the mitochondrial DNA (mtDNA) may result in a disease. One of these diseases is Kearns Sayre syndrome (KSS), described for the first time in 1958, where different large-scale deletions of different sizes and at different positions have been reported in the mitochondrial genome of patients with similar clinical symptoms. In this study, sequences of the mitochondrial genome of three patients with clinic features of KSS were analyzed. Our results revealed the position, heteroplasmy percentage, size of deletions, and their haplogroups. Two patients contained deletions reported previously and one patient showed a new deletion not reported previously. These results display for the first time a systematic analysis of mtDNA variants in the whole mtDNA genome of patients with KSS to help to understand their association with the disease.


Assuntos
DNA Mitocondrial/genética , Genoma Mitocondrial/genética , Síndrome de Kearns-Sayre/genética , Deleção de Sequência/genética , Adolescente , Adulto , Criança , Feminino , Deleção de Genes , Humanos , Masculino , Mitocôndrias/genética , Mutação/genética , Adulto Jovem
17.
Brain ; 142(1): 50-58, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30576410

RESUMO

Physical stress, including high temperatures, may damage the central metabolic nicotinamide nucleotide cofactors [NAD(P)H], generating toxic derivatives [NAD(P)HX]. The highly conserved enzyme NAD(P)HX dehydratase (NAXD) is essential for intracellular repair of NAD(P)HX. Here we present a series of infants and children who suffered episodes of febrile illness-induced neurodegeneration or cardiac failure and early death. Whole-exome or whole-genome sequencing identified recessive NAXD variants in each case. Variants were predicted to be potentially deleterious through in silico analysis. Reverse-transcription PCR confirmed altered splicing in one case. Subject fibroblasts showed highly elevated concentrations of the damaged cofactors S-NADHX, R-NADHX and cyclic NADHX. NADHX accumulation was abrogated by lentiviral transduction of subject cells with wild-type NAXD. Subject fibroblasts and muscle biopsies showed impaired mitochondrial function, higher sensitivity to metabolic stress in media containing galactose and azide, but not glucose, and decreased mitochondrial reactive oxygen species production. Recombinant NAXD protein harbouring two missense variants leading to the amino acid changes p.(Gly63Ser) and p.(Arg608Cys) were thermolabile and showed a decrease in Vmax and increase in KM for the ATP-dependent NADHX dehydratase activity. This is the first study to identify pathogenic variants in NAXD and to link deficient NADHX repair with mitochondrial dysfunction. The results show that NAXD deficiency can be classified as a metabolite repair disorder in which accumulation of damaged metabolites likely triggers devastating effects in tissues such as the brain and the heart, eventually leading to early childhood death.


Assuntos
Hidroliases/deficiência , Doenças Neurodegenerativas/genética , Pré-Escolar , Simulação por Computador , Feminino , Febre/complicações , Febre/metabolismo , Fibroblastos/metabolismo , Vetores Genéticos , Humanos , Hidroliases/genética , Lactente , Cinética , Lentivirus , Masculino , Mitocôndrias/metabolismo , Mutação , NAD/análogos & derivados , NAD/metabolismo , Doenças Neurodegenerativas/complicações , Doenças Neurodegenerativas/metabolismo , Cultura Primária de Células , Sequenciamento Completo do Genoma
18.
BMC Res Notes ; 11(1): 911, 2018 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-30572950

RESUMO

OBJECTIVES: Leber's hereditary optic neuropathy (LHON) is a mitochondrial genetic disease characterized by a variable and reduced penetrance. Individuals carrying a primary LHON-causing mitochondrial DNA (mtDNA) mutation may either remain asymptomatic lifelong, as unaffected carriers, or develop sudden central visual loss that rapidly aggravates over some weeks. Over the years several genetic/environmental triggers able to modulate the risk of developing LHON have been proposed. We provided data supporting a possible correlation between LHON penetrance and the mtDNA copy number, a raw index of mitochondrial mass, whose increase could represent a compensatory response that cells implement to alleviate the pathogenic effect of the primary LHON-causing mtDNA mutations. DATA DESCRIPTION: We collected Italian and Spanish subjects harboring one of the three common LHON primary mutations, either in heteroplasmic or homoplasmic status. For each population we were able to discriminate between affected subjects presenting typical clinical tracts of LHON and LHON-causing mutation carriers showing no symptoms correlated with vision loss. Each subject has been characterized for the presence of a LHON primary mutation, for its status of homoplasmy or heteroplasmy, and for the mtDNA content per cell, expressed as relative mtDNA/nDNA ratio respect to controls. Additional clinical information is present for all the Italian subjects.


Assuntos
Variações do Número de Cópias de DNA/genética , DNA Mitocondrial/genética , Atrofia Óptica Hereditária de Leber/genética , Penetrância , Feminino , Heterozigoto , Humanos , Itália , Masculino , Mutação , Atrofia Óptica Hereditária de Leber/patologia , Atrofia Óptica Hereditária de Leber/fisiopatologia , Linhagem , Espanha
19.
Hum Mol Genet ; 27(23): 4135-4144, 2018 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-30452684

RESUMO

Protein import into mitochondria is facilitated by translocases within the outer and the inner mitochondrial membranes that are dedicated to a highly specific subset of client proteins. The mitochondrial carrier translocase (TIM22 complex) inserts multispanning proteins, such as mitochondrial metabolite carriers and translocase subunits (TIM23, TIM17A/B and TIM22), into the inner mitochondrial membrane. Both types of substrates are essential for mitochondrial metabolic function and biogenesis. Here, we report on a subject, diagnosed at 1.5 years, with a neuromuscular presentation, comprising hypotonia, gastroesophageal reflux disease and persistently elevated serum and Cerebrospinal fluid lactate (CSF). Patient fibroblasts displayed reduced oxidative capacity and altered mitochondrial morphology. Using trans-mitochondrial cybrid cell lines, we excluded a candidate variant in mitochondrial DNA as causative of these effects. Whole-exome sequencing identified compound heterozygous variants in the TIM22 gene (NM_013337), resulting in premature truncation in one allele (p.Tyr25Ter) and a point mutation in a conserved residue (p.Val33Leu), within the intermembrane space region, of the TIM22 protein in the second allele. Although mRNA transcripts of TIM22 were elevated, biochemical analyses revealed lower levels of TIM22 protein and an even greater deficiency of TIM22 complex formation. In agreement with a defect in carrier translocase function, carrier protein amounts in the inner membrane were found to be reduced. This is the first report of pathogenic variants in the TIM22 pore-forming subunit of the carrier translocase affecting the biogenesis of inner mitochondrial membrane proteins critical for metabolite exchange.


Assuntos
Proteínas de Transporte/genética , Mitocôndrias/genética , Proteínas de Transporte da Membrana Mitocondrial/genética , Miopatias Mitocondriais/genética , Criança , DNA Mitocondrial/genética , Feminino , Fibroblastos/metabolismo , Predisposição Genética para Doença , Humanos , Ácido Láctico/líquido cefalorraquidiano , Proteínas de Membrana Transportadoras/genética , Mitocôndrias/patologia , Membranas Mitocondriais/metabolismo , Membranas Mitocondriais/patologia , Miopatias Mitocondriais/líquido cefalorraquidiano , Miopatias Mitocondriais/patologia , Mutação , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genética , Sequenciamento Completo do Exoma
20.
Enferm. infecc. microbiol. clín. (Ed. impr.) ; 36(9): 539-543, nov. 2018. tab, graf
Artigo em Inglês | IBECS | ID: ibc-176829

RESUMO

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


Assuntos
Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Mitocôndrias/genética , Mitocôndrias/metabolismo , Sepse/sangue , Sepse/fisiopatologia , Plaquetas , Estudos Prospectivos , Estudos de Casos e Controles , Sepse/mortalidade , Espanha/epidemiologia , Unidades de Terapia Intensiva
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