COX15 deficiency causes oocyte ferroptosis

Area of Science:

• Mitochondrial biology
• Human genetics
• Reproductive medicine

Background:

• Mitochondrial functions in oocytes differ significantly from somatic cells.
• Key mitochondrial proteins influencing oocyte quality and reproductive lifespan are largely unidentified.

Purpose of the Study:

• To identify mitochondrial genes associated with oocyte defects and female infertility.
• To investigate the role of cytochrome c oxidase assembly protein 15 (COX15) in oocyte health.

Main Methods:

• Whole-exome sequencing in 1,024 women with oocyte defects and 2,868 controls.
• Population and gene-based burden tests for mitochondrial genes.
• Functional studies in yeast, cell lines, and oocyte-specific mouse models.
• Assessment of ferroptosis inhibition using ferrostatin-1.

Main Results:

• Biallelic pathogenic variants in COX15 were identified as a cause of human oocyte ferroptosis and infertility.
• COX15 variants impaired mitochondrial respiration and Fe2+/ROS homeostasis, leading to oocyte ferroptosis.
• Ferrostatin-1 treatment rescued the oocyte ferroptosis phenotype.

Conclusions:

• Pathogenic variants in COX15 cause female infertility through oocyte ferroptosis via impaired mitochondrial function.
• This study expands the spectrum of mitochondrial disorders to include female infertility.
• Findings provide a genetic diagnostic marker for oocyte defects and highlight ferroptosis's role in human oocyte health.