Mitochondrial biogenesis relies on different protein import machinery, as mitochondrial proteins are imported from the cytosol. The mitochondrial intermembrane space assembly (MIA) pathway consists of GFER/ALR and CHCHD4/Mia40, responsible for importing proteins and their oxidative folding inside the mitochondria. The MIA pathway plays an essential role in complex IV (COX IV) biogenesis via importing copper chaperone COX17, associated with the respiratory chain. BPA, an environmental toxicant, found in consumable plastics, causes neurotoxicity via impairment in mitochondrial dynamics, neurogenesis, and cognitive functions. We studied the levels of key regulatory proteins of mitochondrial import pathways and mitochondrial biogenesis after BPA exposure in the rat hippocampus. BPA caused a significant reduction in the levels of mitochondrial biogenesis proteins (PGC1α, and TFAM) and mitochondrial import protein (GFER). Immunohistochemical analysis showed reduced co-localization of NeuN with GFER, PGC-1α, and TFAM suggesting impaired mitochondrial biogenesis and protein import. BPA exposure resulted in damaged mitochondria with distorted cristae in neurons and caused a significant reduction in GFER localization inside IMS as depicted by immunogold electron microscopy. The reduced levels of GFER resulted in defective COX17 import. The translocation of cytochrome c into the cytosol and increased cleaved caspase-3 levels triggered apoptosis due to BPA toxicity. Overall, our study implicates GFER as a potential target for impaired mitochondrial protein machinery, biogenesis, and apoptosis against BPA neurotoxicity in the rat hippocampus.

线粒体生物发生依赖于不同的蛋白质输入机制，因为线粒体蛋白质是从细胞质中输入的。线粒体膜间空间组装 (MIA) 途径由 GFER/ALR 和 CHCHD4/Mia40 组成，负责在线粒体内输入蛋白质及其氧化折叠。 MIA 途径通过导入与呼吸链相关的铜伴侣 COX17，在复合物 IV (COX IV) 生物合成中发挥重要作用。 BPA 是一种环境毒物，存在于消费塑料中，通过损害线粒体动力学、神经发生和认知功能而导致神经毒性。我们研究了大鼠海马接触 BPA 后线粒体输入途径和线粒体生物发生的关键调节蛋白的水平。 BPA 导致线粒体生物发生蛋白（PGC1α 和 TFAM）和线粒体输入蛋白（GFER）的水平显着降低。免疫组织化学分析显示 NeuN 与 GFER、PGC-1α 和 TFAM 的共定位减少，表明线粒体生物发生和蛋白质输入受损。 BPA 暴露导致线粒体受损，神经元嵴扭曲，并导致 IMS 内 GFER 定位显着减少，如免疫金电子显微镜所示。 GFER 水平降低导致 COX17 导入有缺陷。由于 BPA 毒性，细胞色素 c 易位到胞浆中以及裂解的 caspase-3 水平增加引发了细胞凋亡。总体而言，我们的研究表明 GFER 是大鼠海马中线粒体蛋白机制受损、生物发生和细胞凋亡对抗 BPA 神经毒性的潜在靶点。