Diffusion Mechanism Modeling of Metformin in Human Organic Cationic Amino Acid Transporter one and Functional Impact of S189L, R206C, and G401S Mutation.

Metformin used as a first-line drug to treat Type 2 Diabetes Mellitus is transported via organic cation channels to soft tissues. Mutations in the SLC22A1 gene, such as Gly401Ser, Ser189Leu, and Arg206Cys, may affect the drug's therapeutic effect on these patients. This study aims at proposing a potential structural model for drug interactions with the hOCT1 transporter, as well as the impact of these mutations at both topological and electronic structure levels on the channel's surface, from a chemical point of view with, in addition to exploring the frequency distribution. To chemically understand metformin diffusion, we used an open model from the protein model database, with ID PM0080367, viewed through UCSF Chimera. The effect of the mutations was assessed using computational hybrid Quantum Mechanics/Molecular Mechanics, based on the Austin Model 1 semi-empirical method using Spartan 18' software. The results demonstrate coupling energy for metformin with amino acids F, W, H and Y, because of the interaction between the metformin dication and the electron cloud of π orbitals. The mutations analyzed showed changes in the chemical polarity and topology of the structure. The proposed diffusion model is a possible approach to the interaction mechanism between metformin and its transporter, as well as the impacts of variants, suggesting structural changes in the action of the drug. Metformin efficacy considerably varies from one patient to another; this may be largely attributed to the presence of mutations on the SLC22A1 gene. This study aims at proposing a potential structural model for metformin-hOCT1 (SLC22A1) transporter interaction, as well as the identification of the effect of mutations G401S (rs34130495), S189L (rs34104736), and R206C (616C > T) of the SLC22A1 gene at the topological and electronic structure levels on the channel surfaces, from a chemical viewpoint. Our results demonstrated that the coupling energies for metformin with aromatic amino acids F, W, H and Y, because of the interaction between the metformin dication and the electron cloud of π orbitals. Changes in the chemical environment's polarity and the structure's topology were reported in the mutations assessed. The diffusion model proposed is a potential approach for the mechanism of interaction of metformin with its transporter and the effects of variants on the efficacy of the drug in the treatment of type 2 diabetes. The assessment of the frequency of these mutations in a sample of Colombian type 2 diabetes patients suggests that different SLC22A1 gene variants might be involved in reduced OCT1 activity in the Colombian population since none of these mutations were detected.

Evaluation of variants in IL6R, TLR3, and DC-SIGN genes associated with dengue in sampled Colombian population. / Evaluación de variantes en los genes IL6R, TLR3 y DC-SIGN asociadas con dengue en una población colombiana muestreada

INTRODUCTION: Host genetics is recognized as an influential factor for the development of dengue disease. OBJECTIVE: This study evaluated the association of dengue with the polymorphisms rs8192284 for gene IL6R, rs3775290 for TLR3, and rs7248637 for DC-SIGN. MATERIALS AND METHODS: Of the 292 surveyed subjects, 191 were confirmed for dengue fever and the remaining 101 were included as controls. The genotypes were resolved using polymerase chain reaction and restriction fragment length polymorphism (PCRRFLP). In an attempt to determine the risk (Odds Ratio) of suffering dengue fever, data were analyzed using chi-square for alleles and logistic regression for both genotypes and allelic combinations. Confidence intervals were set to 95% for all tests regardless of the adjustment by either self-identification or ancestry. RESULTS: For Afro-Colombians, the allele rs8192284 C offered protection against dengue [OR=0.425,(0.204-0.887), p=0.020]. The alleles rs7248637 A and rs3775290 A posed, respectively, an increased risk of dengue for Afro-Colombians [OR=2.389, (1.170-4.879), p=0.015] and Mestizos [OR=2.329, (1.283-4.226), p=0.005]. The reproducibility for rs8192284 C/C [OR=2.45, (1.05-5.76), p=0.013] remained after adjustment by Amerindian ancestry [OR=2.52, (1.04-6.09), p=0.013]. The reproducibility for rs3775290 A/A [OR=2.48, (1.09-5.65), p=0.033] remained after adjustment by European [OR=2.34, (1.02-5.35), p=0.048], Amerindian [OR=2.49, (1.09-5.66), p=0.035], and African ancestry [OR=2.37, (1.04-5.41), p=0.046]. Finally, the association of dengue fever with the allelic combination CAG [OR=2.07, (1.06-4.05), p=0.033] remained after adjustment by Amerindian ancestry [OR=2.16, (1.09-4.28), p=0.028]. CONCLUSIONS: Polymorphisms rs8192284 for IL6R, rs3775290 for TLR3, and rs7248637 for DC-SIGN were associated with the susceptibility to suffer dengue fever in the sampled Colombian population.

Introducción. La genética del huésped se reconoce como un factor que influye en el desarrollo del dengue. Objetivo. Este estudio evaluó la asociación del dengue con los polimorfismos rs8192284 del gen IL6R, rs3775290 del TLR3 y rs7248637 del DC-SIGN. Materiales y métodos. De los 292 sujetos encuestados, en 191 se confirmó la presencia de fiebre por dengue y los restantes 101 se incluyeron como controles. Los genotipos se resolvieron mediante reacción en cadena de la polimerasa y polimorfismos en la longitud de los fragmentos de restricción (PCR-RFLP). En un intento por determinar el riesgo de sufrir dengue, los datos se analizaron mediante la prueba de ji al cuadrado para los alelos y la regresión logística para los genotipos y las combinaciones alélicas. Los intervalos de confianza se calcularon a 95 % para todas las pruebas independientemente ajustadas por autoidentificación o componente genético ancestral. Resultados. En los afrocolombianos, el alelo C rs8192284 ofreció protección contra el dengue (OR=0,425; 0,204-0,887, p=0,020). Los alelos A rs7248637 y A rs3775290 plantearon un mayor riesgo de dengue para los afrocolombianos (OR=2,389; 1,170-4,879; p=0,015) y los mestizos (OR=2,329; 1,283-4,226: p=0,005), respectivamente. La reproducibilidad para rs8192284 C/C (OR=2,45; 1,05-5,76; p=0,013) permaneció después del ajuste por el componente genético ancestral amerindio (OR=2,52; 1,04-6,09; p=0,013). La reproducibilidad del rs3775290 A/A (OR=2,48; 1,09-5,65; p=0,033) permaneció después del ajuste por el componente europeo (OR=2,34; 1,02-5,35; p=0,048), el amerindio (OR=2,49; 1,09- 5,66; p=0,035), y el africano (OR=2,37; 1,04-5,41; p=0,046). Por último, la asociación del dengue con la combinación alélica CAG (OR=2,07; 1,06-4,05; p=0,033) permaneció después del ajuste por el componente genético amerindio (OR=2,16; 1,09-4,28; p=0,028). Conclusión. Los polimorfismos rs8192284 en IL6R, rs3775290 en TLR3 y rs7248637 en DC-SIGN, se asociaron con la propensión a sufrir dengue en una muestra de población colombiana.

Evaluation of variants in IL6R, TLR3, and DC-SIGN genes associated with dengue in a sampled Colombian population / Evaluación de las variantes en los genes IL6R, TLR3 y DC-SIGN asociadas con dengue en una muestra de población colombiana

Abstract Introduction: Host genetics is recognized as an influential factor for the development of dengue disease. Objective: This study evaluated the association of dengue with the polymorphisms rs8192284 for gene IL6R, rs3775290 for TLR3, and rs7248637 for DC-SIGN. Materials and methods: Of the 292 surveyed subjects, 191 were confirmed for dengue fever and the remaining 101 were included as controls. The genotypes were resolved using polymerase chain reaction and restriction fragment length polymorphism (PCR- RFLP). In an attempt to determine the risk (Odds Ratio) of suffering dengue fever, data were analyzed using chi-square for alleles and logistic regression for both genotypes and allelic combinations. Confidence intervals were set to 95% for all tests regardless of the adjustment by either self-identification or ancestry. Results: For Afro-Colombians, the allele rs8192284 C offered protection against dengue [OR=0.425,(0.204-0.887), p=0.020]. The alleles rs7248637 A and rs3775290 A posed, respectively, an increased risk of dengue for Afro-Colombians [OR=2.389, (1.170-4.879), p=0.015] and Mestizos [OR=2.329, (1.283-4.226), p=0.005]. The reproducibility for rs8192284 C/C [OR=2.45, (1.05-5.76), p=0.013] remained after adjustment by Amerindian ancestry [OR=2.52, (1.04-6.09), p=0.013]. The reproducibility for rs3775290 A/A [OR=2.48, (1.09-5.65), p=0.033] remained after adjustment by European [OR=2.34, (1.02-5.35), p=0.048], Amerindian [OR=2.49, (1.09-5.66), p=0.035], and African ancestry [OR=2.37, (1.04-5.41), p=0.046]. Finally, the association of dengue fever with the allelic combination CAG [OR=2.07, (1.06-4.05), p=0.033] remained after adjustment by Amerindian ancestry [OR=2.16, (1.09-4.28), p=0.028]. Conclusions: Polymorphisms rs8192284 for IL6R, rs3775290 for TLR3, and rs7248637 for DC-SIGN were associated with the susceptibility to suffer dengue fever in the sampled Colombian population.

Resumen Introducción. La genética del huésped se reconoce como un factor que influye en el desarrollo del dengue. Objetivo. Este estudio evaluó la asociación del dengue con los polimorfismos rs8192284 del gen IL6R, rs3775290 del TLR3 y rs7248637 del DC-SIGN. Materiales y métodos. De los 292 sujetos encuestados, en 191 se confirmó la presencia de fiebre por dengue y los restantes 101 se incluyeron como controles. Los genotipos se resolvieron mediante reacción en cadena de la polimerasa y polimorfismos en la longitud de los fragmentos de restricción (PCR-RFLP). En un intento por determinar el riesgo de sufrir dengue, los datos se analizaron mediante la prueba de ji al cuadrado para los alelos y la regresión logística para los genotipos y las combinaciones alélicas. Los intervalos de confianza se calcularon a 95 % para todas las pruebas independientemente ajustadas por autoidentificación o componente genético ancestral. Resultados. En los afrocolombianos, el alelo C rs8192284 ofreció protección contra el dengue (OR=0,425; 0,204-0,887, p=0,020). Los alelos A rs7248637 y Ars3775290 plantearon un mayor riesgo de dengue para los afrocolombianos (OR=2,389; 1,170- 4,879; p=0,015) y los mestizos (OR=2,329; 1,283-4,226: p=0,005), respectivamente. La reproducibilidad para rs8192284 C/C (OR=2,45; 1,05-5,76; p=0,013) permaneció después del ajuste por el componente genético ancestral amerindio (OR=2,52; 1,04- 6,09; p=0,013). La reproducibilidad del rs3775290 A/A (OR=2,48; 1,09-5,65; p=0,033) permaneció después del ajuste por el componente europeo (OR=2,34; 1,02-5,35; p=0,048), el amerindio (OR=2,49; 1,09- 5,66; p=0,035), y el africano (OR=2,37; 1,04- 5,41; p=0,046). Por último, la asociación del dengue con la combinación alélica CAG (OR=2,07; 1,06-4,05; p=0,033) permaneció después del ajuste por el componente genético amerindio (OR=2,16; 1,09-4,28;p=0,028). Conclusión. Los polimorfismos rs8192284 en IL6R, rs3775290 en TLR3 y rs7248637 en DC-SIGN, se asociaron con la propensión a sufrir dengue en una muestra de población colombiana.

Association of Native American ancestry and common variants in ACE, ADIPOR2, MTNR1B, GCK, TCF7L2 and FTO genes with glycemic traits in Colombian population.

Insulin resistance and defects in other related glycemic traits are common findings in the context of Metabolic Syndrome. Although genetic factors are clearly implied in susceptibility, and some gene variants have been identified mainly in populations of European ancestry, little is known about this aspect in admixed populations. The association of insulin resistance, ß-cell function, fasting insulin and glucose levels with 48 gene variants, previously related to metabolic syndrome components, and with the ancestral genetic composition, estimated on 50 ancestry informative markers, was evaluated in 417 individuals from the Colombian admixed population. The Native American genetic ancestry was associated with a low ß-cell function (odds ratio (OR) of 1.73 and 95% confidence interval (95% CI) of 1.07-2.81, p = 0.026). Significant genotypic associations were obtained (q-value < 0.05) for gene variants in ACE (rs4340; OR (95% CI): 2.79 (1.58-4.91), insulin resistance; mean difference (95% CI): 0.273 (0.141; 0.406), fasting insulin), ADIPOR2 (rs11061971; OR (95% CI): 0.14 (0.04-0.48), low ß-cell function), MTNR1B (rs10830963; mean difference (95% CI): 0.032 (0.013; 0.051), fasting glucose) and GCK (rs4607517; mean difference (95% CI): 0.038 (0.020;0.056) and rs1799884; mean difference (95% CI): 0.027 (0.013-0.041), fasting glucose). Also the well-known gene variants rs7903146 in TCF7L2, and rs17817449 in FTO, were nominally associated with hyperglycemia (rs7903146), as well as with higher fasting insulin levels (rs17817449). Our findings indicate that gene variants in ACE, ADIPOR2, MTNR1B, GCK, TCF7L2 and FTO, are associated with glycemic traits in the admixed Colombian population, while a higher Native American genetic component is related to lower ß-cell function.

Insulin resistance and ß-cell function in Colombian mestizo and Embera-Chamí populations and their relation with adiposity degree.

BACKGROUND AND OBJECTIVE: Insulin resistance (IR) is a condition favored by metabolic and endocrine changes experienced by adipose tissue in the context of obesity. The prevalence and the presentation of both IR and obesity vary among the populations, and may be affected by ancestral genetic composition among other factors. The aim of this study was to compare the presence of IR and obesity in Amerindians of the Embera-Chamí ethnicity and Colombian mestizo population. PATIENTS AND METHODS: A sample of 630 individuals, 471 mestizos and 159 Amerindians of the Embera-Chamí ethnicity, from the general population of Colombia were studied. For each participant, anthropometric and biochemical measurements, as well as blood pressure and the Homeostatic Model Assessment (HOMA) of IR and ß-cell function (%B) were recorded. These values were compared between the two populations. RESULTS: While prevalence of central obesity was similar in both populations (48.7% and 42.6% in the mestizo and Embera groups respectively; p=0.148), body mass index (BMI) values suggested a higher prevalence of overweight in the Embera than in mestizo population (43.4% Embera, 31.8% mestizo; p=0.027). Despite the similarities in the prevalence of HOMA-IR and HOMA-%B status between both populations, the Embera population had a significantly greater pancreatic ß-cell function, higher insulin levels, and better glucose control, across BMI and central obesity categories, than the mestizo population. CONCLUSION: There are differences in aspects related to energy metabolism between the samples of the mestizo and Amerindian populations analyzed.

Insulin resistance and Beta-cell function in Colombian mestizo and Embera-Chamí populations and their relation with adiposity degree

Background and objective: Insulin resistance (IR) is a condition favored by metabolic and endocrine changes experienced by adipose tissue in the context of obesity. The prevalence and the presentation of both IR and obesity vary among the populations, and may be affected by ancestral genetic composition among other factors. The aim of this study was to compare the presence of IR and obesity in Amerindians of the Embera-Chamí ethnicity and Colombian mestizo population. Patients and methods: A sample of 630 individuals, 471 mestizos and 159 Amerindians of the Embera-Chamí ethnicity, from the general population of Colombia were studied. For each participant, anthropometric and biochemical measurements, as well as blood pressure and the Homeostatic Model Assessment (HOMA) of IR and β-cell function (%B) were recorded. These values were compared between the two populations. Results: While prevalence of central obesity was similar in both populations (48.7% and 42.6% in the mestizo and Embera groups respectively; p=0.148), body mass index (BMI) values suggested a higher prevalence of overweight in the Embera than in mestizo population (43.4% Embera, 31.8% mestizo; p=0.027). Despite the similarities in the prevalence of HOMA-IR and HOMA-%B status between both populations, the Embera population had a significantly greater pancreatic β-cell function, higher insulin levels, and better glucose control, across BMI and central obesity categories, than the mestizo population. Conclusion: There are differences in aspects related to energy metabolism between the samples of the mestizo and Amerindian populations analyzed (AU)

Antecedentes y objetivo: La resistencia a la insulina (RI) es una condición favorecida por las alteraciones metabólicas y endocrinológicas experimentadas por el tejido adiposo en el contexto de obesidad. Tanto la prevalencia como la presentación de RI y obesidad varían entre las poblaciones y puede ser afectada, entre otros factores, por la composición genética ancestral. El objetivo de este estudio fue comparar la presentación tanto de RI como de obesidad entre amerindios de la etnia embera-chamí y población mestiza colombiana. Pacientes y métodos: Se estudió una muestra de 630 individuos de la población general mestiza colombiana (471 individuos) y de amerindios de la etnia embera-chamí (159 individuos). Para todos los participantes se registraron tanto medidas antropométricas, bioquímicas así como de presión arterial y el índice homeostatic model assessment (HOMA) para la RI y función de la célula β, valores que fueron comparados entre las poblaciones. Resultados: Mientras que ambas poblaciones mostraron una prevalencia de obesidad central similar (48,7% en mestizos, 42,6% en embera; p=0,148), los embera presentaron mayor exceso de peso de acuerdo al índice de masa corporal que los mestizos (43,4% en embera, 31,8% en mestizos; p=0,027). A pesar de las similitudes en la prevalencia de HOMA2-RI y HOMA2- %B entre ambas poblaciones, los embera presentan una función significativamente mayor de las células β del páncreas, niveles de insulina comparativamente mayores y un mejor control glucémico que los mestizos. Conclusión: Existen diferencias en aspectos del metabolismo energético entre las muestras de población mestiza y amerindia analizadas (AU)

Efecto de una intervención con ejercicio físico y orientación nutricional sobre componentes del síndrome metabólico en jóvenes con exceso de peso / Effect of an intervention with physical exercise and nutritional guidance on the components of the metabolic syndrome among young people with overweight

Introducción: las intervenciones con ejercicio físico y orientación nutricional muestran cambios en el exceso de peso en jóvenes con el síndrome metabólico (SM); sin embargo, sus características y resultados son diversos.Objetivo: evaluar el efecto de una intervención con ejercicio físico y orientación nutricional sobre componentes del SM en jóvenes con exceso de peso.Materiales y métodos: estudio longitudinal con una evaluación antes y otra después, en nueve jóvenes entre 11 y 17 años. Se evaluaron aspectos antropométricos, frecuencia cardíaca en reposo (FCR), consumo pico de oxígeno (VO2pico), insulinemia, resistencia a la insulina (HOMA) y componentes de SM. La intervención consistió en 12 semanas de ejercicio supervisado, tres sesiones/semana de 90 minutos (aeróbico y de fuerza), más dos sesiones no supervisadas; el suministro semanal de frutas y verduras para cubrir las cinco porciones diarias recomendadas y educación nutricional individual y colectiva.Resultados: luego de la intervención disminuyeron la circunferencia de la cintura de 90,5 ± 11,0 a 88,1 ± 9,9 cm; el IMC de 30,2 ± 5,8 a 29,3 ± 5,6 kg/m2; la grasa corporal total de 39,8 ± 13,0 a 34,3 ± 9,0%; la glucemia de 86,0 ± 8,6 a 83,1 ± 5,0 mg/dL; la insulinemia de 23,2 ± 9,8 a 19,4 ± 7,6 µU/mL; el HOMA-IR de 2,89 ± 1,21 a 2,39 ± 0,93; la FCR de 87,9 ± 4,3 a 78,2 ± 5,5 bpm y aumentó el VO2pico de 36,3 ± 5,1 a 38,5 ± 4,1 mL/kg/min; de seis jóvenes con diagnóstico de SM al inicio, cuatro no lo presentaron al final.Conclusiones: participar en un programa de ejercicio y aumentar el consumo de frutas y verduras en los jóvenes con exceso de peso y componentes del SM generó modificaciones positivas en la composición corporal, el VO2pico, la FCR y la glucemia así como en los componentes y prevalencia del SM.

Introduction: Interventions with physical exercise and nutritional guidance show changes in overweight among young people suffering from the metabolic syndrome (MS); nevertheless, their characteristics and results vary.Objective: To assess the effect of an intervention with physical exercise and nutritional guidance on components of the MS among overweighted young people.Materials and methods: Longitudinal study with an assessment before and another after the intervention in nine young people aged 11 to 17 years. Anthropometric aspects, resting heart rate, peak oxygen consumption (VO2peak), insulinemia, HOMA, and components of the MS were assessed. Intervention consisted of 12 weeks of supervised exercise, three 90-minute sessions/week (aerobic and strength), plus two unsupervised sessions; the weekly supply of fruits and vegetables in order to cover the five recommended daily servings, and individual and group nutrition education.Results: With the intervention waist circumference decreased from 90.5 ± 11.0 to 88.1 ± 9.9 cm; BMI from 30.2 ± 5.8 to 29.3 ± 5.6 kg/m2; total body fat from 39.8 ± 13.0 to 34.3 ± 9.0%; glycemia from 86.0 ± 8.6 to 83.1 ± 5.0 mg/dL; insulinemia from 23.2 ± 9.8 to 19.4 ± 7.6 µU/mL; HOMA-IR from 2.89 ± 1.21 to 2.39 ± 0.93; resting heart rate from 87.9 ± 4.3 to 78.2 ± 5.5 rpm, and VO2peak increased from 36.3 ± 5.1 to 38.5 ± 4.1 mL/kg/min. Four out of six young people with the diagnosis of MS at the beginning of the study did not present it at the end.Conclusions: Participating in an exercise program and increase in the consumption of fruits and vegetables among overweighted young people with components of the MS produced positive modifications in body composition, VO2peak, resting heart rate, and glycemia, as well as in the components and prevalence of the MS.

Comportamiento de la mutación mtDNA A3243G en dos familas antioqueñas de pacientes diagnosticados con el síndrome MELAS / Behavior of the mtDNA mutation A3243 in two antioquian families of patients with melas syndrome

Introducción: mutaciones en mtDNA causan citopatias mitocondriales, la más común de ellases el síndrome MELAS; la transición A3243G en tRNA de leucina (tRNALeu) se presenta en 80% depacientes. La heteroplasmia, observada en citopatias mitocondriales, consiste en coexistenciade moléculas mutadas y normales en una célula, situación en la cual, dependiendo de su cantidad,afecta su función con expresión clínica variable.Objetivo: evaluar el comportamiento de la cantidad de heteroplasmia de la mutación 3243G ensu expresión clínica y en la dependencia de variantes nucleares.Pacientes y métodos: se buscaron mutaciones en el gen que codifica para el tRNA de leucinapor secuencia y por PCR-RFLP en 34 pacientes, y se tamizó en familiares de los portadores de lamutación. Se tipificaron cuatro Specific Population Allele (SPA) en pacientes y familiares con lamutación A3243G.Resultados: se halló la mutación A3243G en el tRNALeu en dos pacientes, luego de tamizar lamutación A3243G en ambas familias se evaluó la cantidad de mtDNA mutado (MDNA),encontrando que los casos índices de ambas familias presentaron la mayor cantidad de MDNA;en la primera familia se detectó la mutación en 15 miembros que presentaron diversos síntomas.En la segunda familia se detectó la mutación en un miembro con parálisis cerebral, en dos conmigraña y en uno asintomático.Conclusiones: la severidad de los síntomas se correlaciona con la cantidad de MDNA, se encontróademás correlación entre mtDNA mutado (MDNA) y el Índice de Ancestría Amerindio en cadaindividuo (IAA), indicando una posible influencia del contexto nuclear amerindio en lasegregación y replicación mitocondrial.

Mitochondrial DNA mutations cause mitochondrialcytopathies. Among them Mitochondrial Encephalomyopathy,Lactic Acidosis, and Stroke-like episodes(MELA) is the commonest. The transition 3243A>G inthe Leucine tRNA is present in 80% of the patients.Heteroplasmy is observed in mitochondrialcytopathies, characterized by the coexistence of mutantand wild type molecules in a cell. Depending on thelevel of heteroplasmy, function and clinicalmanifestations might result affected.Objective: To test the degree of heteroplasmy of themutation 3243G on its expression (syntoms) andnuclear-variants dependence.Patients and methods: Mutations in the tRNALeu genewere sought in 34 patients by sequencing and PCR-RFLP.Four SPA (specific population alleles) were typed inpatients and their relatives carrying the mutation3243A>G.Results: The mutation 3243A>G in the Leucine tRNAgene was found in two patients. This mutation wasscreened in their relatives and the amount of mutantDNA (MDNA) was assessed. The index cases presentedwith the higher amounts of MDNA in both families. Infamily one, the mutation was detected in 14members, three of which presented with short stature,one with hearing loss, one with type 2 diabetes, 8 withmigraine and one healthy individual. In family two themutation was detected in one member with brainparalysis, two with migraine and one healthyindividual.Conclusions: Severity of the symptoms in patientsaffected with MELAS is correlated with the amount ofMDNA. Furthermore, it was found a correlationbetween MDNA and IAA, suggesting a possible effect ofamerind nuclear ontext in The mitochondrialsegregation and replication.