Exposure to benzo(a)pyrene suppresses mitophagy via ANT1-PINK1-Parkin pathway in ovarian corpus luteum during early pregnancy.

Nanyan Li, Hanting Xu, Xueqing Liu, Rufei Gao, Junlin He, Yubin Ding, Fangfang Li, Yanqing Geng, Xinyi Mu, Xuemei Chen

The Science of the total environment 2022 Mar 25

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Exposure to benzo (a)pyrene (BaP) has been confirmed to interfere with embryo implantation. As the primary organ of progesterone synthesis during early pregnancy, the ovarian corpus luteum (CL) is essential for embryo implantation and pregnancy maintenance. We previously demonstrated that BaP impaired luteal function, but the molecular mechanism remains unclear. In CL cells, mitochondria are the main sites of progesterone synthesis. Mitophagy, a particular type of autophagy, regulates mitochondrial quality by degrading damaged mitochondria and ensuring the homeostasis of cell physiology. Therefore, the present study investigated the effects and the potential molecular mechanisms of BaP on ovarian mitophagy during early pregnancy. We found that BaP and its metabolite, BPDE, inhibited autophagy and PINK1/Parkin-mediated mitophagy in the pregnant ovaries and luteinized granulosa cell, KGN. Notably, adenine nucleotide translocator 1 (ANT1), a crucial mediator of PINK1-dependent mitophagy, was suppressed by BaP and BPDE both in vivo and in vitro. The inhibition of ANT1 leads to the decrease in the PINK1 bound to the outer membrane of mitochondria and consequently reduces recruitment of Parkin to the mitochondria, which is required for the subsequent clearance of mitochondria. Meanwhile, exposure to BPDE also damaged mitochondrial function, causing the reduction in mitochondrial potential and ATP production. Overexpression of ANT1 in KGN cells partially relieved the inhibition of mitophagy caused by BPDE, restored mitochondrial function and expression of hormone synthesis-associated genes. Collectively, our study firstly clarified that BaP and BPDE suppress mitophagy of CL cells via the ANT1-PINK1-Parkin pathway, which provides a new insight to explore the detailed mechanism of the BaP-induced ovarian toxicity. Copyright © 2022 Elsevier B.V. All rights reserved.

Citation

Nanyan Li, Hanting Xu, Xueqing Liu, Rufei Gao, Junlin He, Yubin Ding, Fangfang Li, Yanqing Geng, Xinyi Mu, Xuemei Chen. Exposure to benzo(a)pyrene suppresses mitophagy via ANT1-PINK1-Parkin pathway in ovarian corpus luteum during early pregnancy. The Science of the total environment. 2022 Mar 25;814:152759