Type 2 diabetes increases oocyte mtDNA mutations which are eliminated in the offspring by bottleneck effect

Area of Science:

• Reproductive biology
• Mitochondrial genetics
• Diabetes research

Background:

• Diabetes mellitus is linked to various complications, including impaired fertility and diminished oocyte quality.
• The impact of diabetes on mitochondrial DNA (mtDNA) mutations in oocytes remains largely unexplored.

Purpose of the Study:

• To investigate whether type 2 diabetes (T2D) increases mtDNA mutations in mouse oocytes.
• To determine if these mutations are transmitted to offspring and if the mitochondrial bottleneck effect plays a role.

Main Methods:

• A mouse model for T2D was established using a high-fat diet (HFD) and streptozotocin (STZ) injection.
• High-throughput sequencing was employed to analyze mtDNA mutations in oocytes from diabetic and control mice.
• mtDNA mutations were also examined in the offspring (F1 generation) of diabetic mice.

Main Results:

• T2D mice exhibited characteristic symptoms including glucose intolerance, insulin resistance, and reduced fecundity compared to controls.
• Oocytes from T2D mice displayed a significant increase in both the number of mtDNA mutation sites and the overall mutation count.
• Analysis of F1 offspring revealed that the mitochondrial bottleneck mechanism effectively eliminated the increased mtDNA mutations observed in the diabetic mothers.

Conclusions:

• T2D is associated with elevated mtDNA mutation sites and numbers in oocytes.
• The adverse effects of T2D-induced mtDNA mutations on oocytes can be mitigated in offspring through the mitochondrial bottleneck effect.
• This study provides novel insights into mtDNA mutations in oocytes of diabetic mothers and their offspring, utilizing a sensitive method with a small number of oocytes.