Atomoxetine (ATX) is a presynaptic norepinephrine transporter (NET) inhibitor widely prescribed for attention-deficit/hyperactivity disorder (ADHD) due to its low abuse potential and absence of psychostimulant effects. While NET inhibition is implicated in the clinical response, several additional pharmacoactivities may contribute to clinical efficacy or unwanted side effects. We recently reported that ATX can dose-dependently alter mitochondrial function and cellular redox status. Here, we assessed potential alterations in mitochondrial biogenesis, mitochondrial dynamics and cellular antioxidant capacity following high- and low-dose ATX treatment of differentiated human neuroblastoma cells. Human SH-SY5Y neuroblastoma cells were treated with ATX (1, 5, 10, 20 and 50 μM) for 7 days under differentiation culture conditions. Changes in the expression levels of protein markers for mitochondrial biogenesis, fusion and fission as well as of antioxidant proteins were analysed by Western blot. High-dose ATX (50 μM) reduced while low-dose ATX (10 μM) increased mitochondrial biogenesis as evidenced by parallel changes in SDHA, COX-I, PGC1α and TFAM expression. High-dose ATX also reduced mitochondrial fusion as evidenced by OPA1 and MFN2 downregulation, and mitochondrial fission as indicated by DRP1 and Fis1 downregulation. In contrast, ATX did not alter expression of the antioxidant enzymes SOD1 and catalase, the phase II transcription factor Nfr2, or the Nfr2-regulated antioxidant enzyme NQO1. Clinical responses and side effects of ATX may be mediated by dose-dependent modulation of mitochondrial biogenesis and dynamics as well as NET inhibition.

Atomoxetine (ATX) 是一种突触前去甲肾上腺素转运蛋白 (NET) 抑制剂，由于其滥用可能性低且没有精神兴奋剂作用，因此广泛用于注意力缺陷/多动障碍 (ADHD)。虽然 NET 抑制与临床反应有关，但一些额外的药物活性可能有助于临床疗效或不良副作用。我们最近报道，ATX 可以剂量依赖性地改变线粒体功能和细胞氧化还原状态。在这里，我们评估了高剂量和低剂量 ATX 处理分化的人神经母细胞瘤细胞后线粒体生物发生、线粒体动力学和细胞抗氧化能力的潜在变化。在分化培养条件下，用 ATX（1、5、10、20 和 50 μM）处理人 SH-SY5Y 神经母细胞瘤细胞 7 天。通过蛋白质印迹分析线粒体生物发生、融合和裂变以及抗氧化蛋白的蛋白质标记表达水平的变化。SDHA、COX-I、PGC1α 和 TFAM 表达的平行变化证明了高剂量 ATX (50 μM) 减少而低剂量 ATX (10 μM) 增加了线粒体生物合成。OPA1 和 MFN2 下调证明了高剂量 ATX 还减少了线粒体融合，DRP1 和 Fis1 下调表明了线粒体裂变。相反，ATX 不改变抗氧化酶 SOD1 和过氧化氢酶、II 期转录因子 Nfr2 或 Nfr2 调节的抗氧化酶 NQO1 的表达。ATX 的临床反应和副作用可能由线粒体生物发生和动力学的剂量依赖性调节以及 NET 抑制介导。