The Involvement of Mitochondrial Dysfunction during the Development of Adenomyosis.

Abstract

The etiology of adenomyosis remains unclear. The association between epithelial-mesenchymal transition (EMT) and mitochondrial dysfunction has been proposed to be involved in fibrotic diseases. Adenomyosis is defined as the existence of endometrial glands and stroma in the myometrium with EMT and ultimate fibrosis. Thus, we aimed to investigate the involvement of mitochondrial dysfunction in fibrotic adenomyosis. Mitochondrial integrity was examined in mouse and human adenomyotic tissues. Control and tamoxifen-treated mice were treated with 3-nitropropionic acid (a mitochondrial dysfunction inducer) and NG-nitro-L-arginine methyl ester (a mitochondrial dysfunction inhibitor), respectively, at postnatal day 21, followed by an evaluation of adenomyosis, EMT and fibrosis as well as the expression of mitophagy, oxidative stress, and transforming growth factor-β1 (TGF-β1). The gene profiles of adenomyotic uteri were examined at postnatal day 42. Adenomyotic mice exhibited increased development of EMT and fibrosis. Adenomyotic tissues showed consistent mitochondrial destruction with increased fission, mitophagosomes, and lysosomes. Besides, mitophagy, oxidative stress, and TGF-β1 levels were consistently increased. The mitochondrial dysfunction, the development of mitophagy and fibrosis, and TGF-β1 expression were induced by 3-nitropropionic acid in control uteri. In contrast, NG-nitro-L-arginine methyl ester attenuated mitochondrial dysfunction, mitophagy, fibrosis, and TGF-β1 in adenomyotic uteri. Gene profiling demonstrated increased expression of mitochondrial dysfunction-related genes in adenomyotic uteri. We showed that mitochondrial dysfunction-induced TGF-β1 dysregulation and fibrosis were associated with the development of adenomyosis.