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-tRNA^Leu(UUR) A3302G and C3275A mutations, mt-tRNA^Gln T4363C and T4395C mutations, mt-tRNA^Ser(UCN) C7492T mutation, mt-tRNA^Asp A7543G mutation, mt-tRNA^Lys A8343G mutation, mt-tRNA^Arg T10454C mutation and mt-tRNA^Glu 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.