Mohapatra Saswat, Das Gaurav, Gupta Varsha, Mondal Prasenjit, Nitani Masashi, Ie Yutaka, Chatterjee Shreyam, Aso Yoshio, Ghosh Surajit
Organic and Medicinal Chemistry Division, CSIR-Indian Institute of Chemical Biology, 4, Raja S. C. Mullick Road, Jadavpur, Kolkata 700032, West Bengal, India.
Academy of Scientific and Innovative Research (AcSIR), CSIR-Indian Institute of Chemical Biology Campus, 4 Raja S. C. Mullick Road, Kolkata 700 032, India.
ACS Omega. 2021 Mar 10;6(11):7815-7828. doi: 10.1021/acsomega.1c00308. eCollection 2021 Mar 23.
Here, we demonstrate an interesting strategy of modulating mitochondrial reactive oxygen species (ROS) using the organic electron acceptor molecule carbonyl-bridged bithiazole attached with bis-trifluoroacetophenone (BBT). This molecule was found to affect complex I activity. It has the propensity to bind close to the flavin mononucleotide site of complex I of mitochondria where it traps electron released from nicotinamide adenine dinucleotide (NADH) and elevates intracellular ROS, which suggests that the bridged carbonyl in BBT plays a crucial role in the acceptance of electron from NADH. We understand that the potential of the NADH/NAD+ redox couple and low-lying LUMO energy level of BBT are compatible with each other, thus favoring its entrapment of released electrons in complex I. This effect of BBT in ROS generation activates JNK and p38 stress-dependent pathways and resulted in mitochondrial-dependent apoptotic cell death with the reduction in expression of several important cyto-protecting factors (Hsp27 and NFκB), indicating its potential in inhibition of cancer cell relapse. Intriguingly, we found that BBT is not a P-glycoprotein substrate, which further reveals its excellent anticancer potential. This study enlightens us on how the power of electron acceptor ability became an emerging strategy for modulation of intracellular function.
在此，我们展示了一种有趣的策略，即使用与双三氟苯乙酮相连的有机电子受体分子羰基桥连双噻唑（BBT）来调节线粒体活性氧（ROS）。发现该分子会影响复合体I的活性。它倾向于结合在线粒体复合体I的黄素单核苷酸位点附近，在那里它捕获从烟酰胺腺嘌呤二核苷酸（NADH）释放的电子并提高细胞内ROS水平，这表明BBT中的桥连羰基在从NADH接受电子方面起着关键作用。我们了解到，NADH/NAD+氧化还原对的电位与BBT的低LUMO能级相互兼容，因此有利于其捕获复合体I中释放的电子。BBT在ROS生成中的这种作用激活了JNK和p38应激依赖性途径，并导致线粒体依赖性凋亡细胞死亡，同时几种重要的细胞保护因子（Hsp27和NFκB）的表达降低，表明其在抑制癌细胞复发方面的潜力。有趣的是，我们发现BBT不是P-糖蛋白底物，这进一步揭示了其出色的抗癌潜力。这项研究让我们了解到电子受体能力如何成为调节细胞内功能的一种新兴策略。
