小柯机器人

美国加州大学Yuriy Kirichok和Michael Grabe团队合作研究发现，线粒体解偶联剂通过激活ADP/ATP载体(AAC)和解偶联蛋白1(UCP1)诱导H⁺泄漏。相关论文于2022年5月25日发表在《自然》杂志上。

研究人员对2,4-二硝基苯酚(DNP)、氰化物-4-(三氟甲氧基)苯腙(FCCP)和其他常见质子载体诱导的I_H进行了直接测量，发现其依赖于AAC和UCP1。基于AAC的分子结构，研究人员通过计算分析以确定质子载体和长链脂肪酸的结合位点，并发现它们与推定的ADP/ATP结合位点重叠。研究人员还设计了一个数学模型，通过该模型推算了由AAC诱导的解耦器依赖的I_H机制。因此，常见质子解偶联剂是通过AAC和UCP1合成I_H激活剂，这为研发靶向这两种线粒体生物能量学中心新型、特异性激活剂铺平了道路。

据悉，线粒体通过H⁺穿过(I_H)其内膜产生热量。I_H是由棕色脂肪中UCP1和其他组织中AAC对长链脂肪酸作用产生，但对其潜在的机制知之甚少。由于缺乏UCP1和AAC对 I_H药理激活剂的证据，I_H被认为是由如DNP和FCCP质子载体诱导的。尽管在动物模型中质子载体对抗肥胖、糖尿病和脂肪肝具有一定的潜力，但由于非选择地增加跨所有生物膜的H⁺电导会产生副作用，它们在人类疾病的治疗过程中作用有限。

附：英文原文

Title: Mitochondrial uncouplers induce proton leak by activating AAC and UCP1

Author: Bertholet, Ambre M., Natale, Andrew M., Bisignano, Paola, Suzuki, Junji, Fedorenko, Andriy, Hamilton, James, Brustovetsky, Tatiana, Kazak, Lawrence, Garrity, Ryan, Chouchani, Edward T., Brustovetsky, Nickolay, Grabe, Michael, Kirichok, Yuriy

Issue&Volume: 2022-05-25

Abstract: Mitochondria generate heat due to H+ leak (IH) across their inner membrane1. IH results from the action of long-chain fatty acids on uncoupling protein 1 (UCP1) in brown fat2,3,4,5,6 and ADP/ATP carrier (AAC) in other tissues1,7,8,9, but the underlying mechanism is poorly understood. As evidence of pharmacological activators of IH through UCP1 and AAC is lacking, IH is induced by protonophores such as 2,4-dinitrophenol (DNP) and cyanide-4-(trifluoromethoxy) phenylhydrazone (FCCP)10,11. Although protonophores show potential in combating obesity, diabetes and fatty liver in animal models12,13,14, their clinical potential for treating human disease is limited due to indiscriminately increasing H+ conductance across all biological membranes10,11 and adverse side effects15. Here we report the direct measurement of IH induced by DNP, FCCP and other common protonophores and find that it is dependent on AAC and UCP1. Using molecular structures of AAC, we perform a computational analysis to determine the binding sites for protonophores and long-chain fatty acids, and find that they overlap with the putative ADP/ATP-binding site. We also develop a mathematical model that proposes a mechanism of uncoupler-dependent IH through AAC. Thus, common protonophoric uncouplers are synthetic activators of IH through AAC and UCP1, paving the way for the development of new and more specific activators of these two central mediators of mitochondrial bioenergetics.

DOI: 10.1038/s41586-022-04747-5

Source: https://www.nature.com/articles/s41586-022-04747-5

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