National Center for Internatinal Research on Animal Gut Nutrition, Jingsu Key Laboratory of Gastrointestinal Nutrition and Animal Health, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095, China.
Nutrigenomics and Growth Biology Laboratory, Department of Animal Sciences, Washington State University, Pullman, WA, 99164, USA.
Adv Sci (Weinh). 2024 May;11(20):e2307480. doi: 10.1002/advs.202307480. Epub 2024 Mar 18.
Due to the exclusive maternal transmission, oocyte mitochondrial dysfunction reduces fertility rates, affects embryonic development, and programs offspring to metabolic diseases. However, mitochondrial DNA (mtDNA) are vulnerable to mutations during oocyte maturation, leading to mitochondrial nucleotide variations (mtSNVs) within a single oocyte, referring to mtDNA heteroplasmy. Obesity (OB) accounts for more than 40% of women at the reproductive age in the USA, but little is known about impacts of OB on mtSNVs in mature oocytes. It is found that OB reduces mtDNA content and increases mtSNVs in mature oocytes, which impairs mitochondrial energetic functions and oocyte quality. In mature oocytes, OB suppresses AMPK activity, aligned with an increased binding affinity of the ATF5-POLG protein complex to mutated mtDNA D-loop and protein-coding regions. Similarly, AMPK knockout increases the binding affinity of ATF5-POLG proteins to mutated mtDNA, leading to the replication of heteroplasmic mtDNA and impairing oocyte quality. Consistently, AMPK activation blocks the detrimental impacts of OB by preventing ATF5-POLG protein recruitment, improving oocyte maturation and mitochondrial energetics. Overall, the data uncover key features of AMPK activation in suppressing mtSNVs, and improving mitochondrial biogenesis and oocyte maturation in obese females.
由于母系遗传，卵母细胞线粒体功能障碍降低了生育能力，影响胚胎发育，并使后代易患代谢疾病。然而，线粒体 DNA（mtDNA）在卵母细胞成熟过程中容易发生突变，导致单个卵母细胞内的线粒体核苷酸变异（mtSNVs），即 mtDNA 异质性。肥胖（OB）在美国占育龄妇女的 40%以上，但人们对 OB 对成熟卵母细胞中 mtSNVs 的影响知之甚少。研究发现，OB 降低了成熟卵母细胞中的 mtDNA 含量并增加了 mtSNVs，这损害了线粒体的能量功能和卵母细胞的质量。在成熟卵母细胞中，OB 抑制 AMPK 活性，同时 ATF5-POLG 蛋白复合物与突变的 mtDNA D 环和蛋白编码区的结合亲和力增加。同样，AMPK 敲除增加了 ATF5-POLG 蛋白与突变 mtDNA 的结合亲和力，导致异质性 mtDNA 的复制，并损害卵母细胞的质量。一致地，AMPK 激活通过阻止 ATF5-POLG 蛋白募集来阻止 OB 的有害影响，从而改善卵母细胞成熟和线粒体能量代谢。总的来说，这些数据揭示了 AMPK 激活在抑制 mtSNVs、改善肥胖女性的线粒体生物发生和卵母细胞成熟方面的关键特征。
