# Polycystic Ovary Syndrome May Be Associated With a Novel Mitochondrial tRNAAsp Mutation

## TL;DR

A new mitochondrial tRNA mutation is linked to polycystic ovary syndrome and insulin resistance, affecting mitochondrial function and increasing oxidative stress.

## Contribution

A novel mitochondrial tRNAAsp mutation (m.7544C>T) is identified as a potential contributor to PCOS-IR through mitochondrial dysfunction.

## Key findings

- The m.7544C>T mutation disrupts tRNAAsp structure and reduces its steady-state levels.
- The mutation impairs mitochondrial respiratory chain enzyme activity and oxygen consumption rates.
- The mutation increases oxidative stress and is associated with PCOS-IR pathophysiology.

## Abstract

Polycystic ovary syndrome is a common clinical condition often linked to insulin resistance (IR) and primarily affects women at reproductive age. Previous research has indicated a close association between mitochondrial tRNA (mt-tRNA) mutations and this syndrome; however, the range of mt-tRNA mutations in PCOS-IR remains largely unclear. In this study, we examined mt-tRNA mutations in 302 Han Chinese women with PCOS-IR and 589 control subjects, identifying a novel m.7544C>T mutation potentially related to this syndrome. At the molecular level, the m.7544C>T mutation occurs at a highly conserved nucleotide within the anticodon stem of mt-tRNAAsp, disrupting the 30C-40G base-pairing. Using cybrids cells derived from two individuals carrying this mutation and two controls without it, we observed that the m.7544C>T decreased the steady-state levels of tRNAAsp, altered mitochondrial RNA transcripts, impaired the activities of respiratory chain enzymes and oxygen consumption rates (OCRs), compromised mitochondrial functions, and increased oxidative stress. Overall, our findings strongly suggest that the m.7544C>T mutation contributes to the development of PCOS-IR, offering new insights into the pathophysiology of PCOS-IR driven by tRNA mutation–induced mitochondrial dysfunction and oxidative stress.