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Mutations in mitochondrial tRNA genes may be related to insulin resistance in women with polycystic ovary syndrome.

ABSTRACT: Polycystic ovary syndrome (PCOS) is a very common endocrine disorder affecting women of reproductive age. Insulin resistance (IR), a central component of this disease, occurs in 30%-40% of women with PCOS. To date, the molecular mechanism underlying PCOS-IR remains largely unknown. Most recently, increasing evidence has shown that mitochondrial dysfunction caused by mitochondrial DNA (mtDNA) mutations plays important roles in the pathogenesis of PCOS-IR. To identify the contribution of mitochondrial tRNA (mt-tRNA) mutations in this disease, we screened 80 women with PCOS-IR and 50 healthy control participants for mt-tRNA mutations. After genetic amplification and direct sequencing, we identified nine mt-tRNA mutations that were potentially associated with PCOS-IR: mt-tRNALeu(UUR) A3302G and C3275A mutations, mt-tRNAGln T4363C and T4395C mutations, mt-tRNASer(UCN) C7492T mutation, mt-tRNAAsp A7543G mutation, mt-tRNALys A8343G mutation, mt-tRNAArg T10454C mutation and mt-tRNAGlu A14693G mutation. These mutations were localized at evolutionarily conserved nucleotides and altered the secondary structure of mt-tRNAs, thus resulting in failure of mt-tRNA metabolism. Moreover, molecular and biochemical analysis revealed that levels of 8-OHdG, malondialdehyde and reactive oxygen species were increased in patients with PCOS-IR carrying these mt-tRNA mutations compared with in healthy control participants, whereas superoxide dismutase levels, mitochondrial copy number, membrane potential and ATP levels were significantly reduced. Taken together, our data indicate that mt-tRNAs are key locations for pathogenic mutations associated with PCOS-IR. Mitochondrial dysfunction caused by mt-tRNA mutations may be involved in the pathogenesis of PCOS-IR. Thus, our findings provide novel insight into the pathophysiology of this disorder.

SUBMITTER: Ding Y

PROVIDER: S-EPMC5489898 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Mutations in mitochondrial tRNA genes may be related to insulin resistance in women with polycystic ovary syndrome.

Ding Yu Y Xia Bo-Hou BH Zhang Cai-Juan CJ Zhuo Guang-Chao GC

American journal of translational research 20170615 6

Polycystic ovary syndrome (PCOS) is a very common endocrine disorder affecting women of reproductive age. Insulin resistance (IR), a central component of this disease, occurs in 30%-40% of women with PCOS. To date, the molecular mechanism underlying PCOS-IR remains largely unknown. Most recently, increasing evidence has shown that mitochondrial dysfunction caused by mitochondrial DNA (mtDNA) mutations plays important roles in the pathogenesis of PCOS-IR. To identify the contribution of mitochond ...[more]

PMID: 28670386

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Project description:BackgroundPolycystic ovary syndrome (PCOS) is strongly associated with abdominal obesity and insulin resistance and effective approaches to nutrition (e.g., omega-3 fatty acids intake) might improve the cardiometabolic risk profile. This study aimed to examine the associations of dietary and serum omega-3 fatty acids with insulin resistance (IR) and body composition among PCOS patients.MethodsA total of 185 patients with PCOS were included in our analysis. Dietary information was collected through face-to-face interviews using a 102-item food frequency questionnaire (FFQ). Serum omega-3 fatty acid levels were measured with the gas chromatography method. Body composition was measured by both dual-energy X-ray absorptiometry (DXA) and bioelectrical impedance (BIA) methods. The multivariable linear regression model was applied to analyze the associations of dietary and serum omega-3 fatty acids with the levels of Homeostasis Model Assessment for Insulin Resistance (HOMA-IR) and body composition parameters among PCOS patients.ResultsOur results indicated that the dietary long-chain omega-3 polyunsaturated fatty acids (PUFA) intakes were negatively associated with HOMA-IR (β = -0.089, P = 0.040), fat mass (β = -0.022, P = 0.047), and body fat percentage (β = -0.026, P = 0.032). For serum biomarkers, higher total omega-3 PUFAs levels (β = -0.158, P = 0.021) and long-chain omega-3 PUFAs levels (β = -0.187, P < 0.001), particularly eicosapentaenoic acid (EPA) (β = -164, P = 0.011) and docosahexaenoic acid (DHA) (β = -0.158, P = 0.001) were also associated with decreased HOMA-IR. In addition, generally, dietary and serum long-chain omega-3 PUFA levels, DPA, and DHA levels were both positively associated with muscle mass measured by DXA; whereas serum total, long-chain and individual omega-3 PUFA levels (e.g., DPA, EPA, and DHA) were all negatively associated with fat mass and body fat percentage. These findings were further confirmed by the findings for body composition measured by the BIA method.ConclusionHigher levels of dietary and serum omega-3 PUFAs, particularly long-chain omega PUFAs (DPA and DHA), might have beneficial effects on metabolic parameters and body composition among PCOS patients.

Project description:Background: Polycystic ovary syndrome (PCOS) is commonly associated with metabolic abnormalities such as hyperinsulinemia, insulin resistance and obesity. The genetic variants of genes regulating insulin action, expression and regulation are suggested as possible factors involved in development and severity of clinical manifestations in PCOS. Aim: We investigated whether IRS-1Gly972Arg (rs1801278) polymorphism is associated with increased risk of PCOS in Kashmiri women. The correlation of various clinical, metabolic and hormonal markers with rs1801278 single nucleotide polymorphism was analyzed. The genotypic−phenotypic association of clinical manifestations of PCOS with the tested genetic variant was also assessed. Results: There were no significant differences in allele frequency (OR = 0.87, CI = 0.59−1.29, χ2 = 0.456, p = 0.499) or genotypic distribution (χ2 = 3.73, p = 0.15) between PCOS women and controls. No significant association was also found in the dominant (OR = 1.63, χ2 = 0.377, p = 0.53), recessive (OR = 0.79, χ2 = 1.01, p = 0.31) or heterozygote vs. homozygote (OR = 1.34, χ2 = 1.53, p = 0.22) genotype model analysis. The genotype−phenotype correlation analysis showed that the Arg allele was significantly associated with increased central adiposity markers hip circumference (p = 0.012), and body adiposity index BAI (p = 0.002) in the recessive model in PCOS women. The two-hour glucose (p = 0.04) and insulin resistance marker HOMA (p = 0.44) were significantly higher in Arg allele carriers. The androgen excess markers dehydroepiandrosterone sulfate DHEAS (p = 0.02), Ferriman−Gallwey score (p = 0.012), prevalence of acne, alopecia and hirsutism (all p < 0.01) were significantly elevated in the wild-type GG genotype. Conclusions:IRS-1Gly972Arg genetic variant does not increase the risk of PCOS in Kashmiri women. However, this polymorphism is associated with clinical manifestations of insulin resistance, obesity and hyperandrogenism, suggesting its possible role in variable phenotypic manifestations of PCOS.

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Mutations in mitochondrial tRNA genes may be related to insulin resistance in women with polycystic ovary syndrome.

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Mutations in mitochondrial tRNA genes may be related to insulin resistance in women with polycystic ovary syndrome.

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