Abstract：
Following structural determination by recent advances in electron cryomicroscopy, it is now well established that the respiratory Complexes I-IV in oxidative phosphorylation (OXPHOS) are organized into supercomplexes in the respirasome. Nonetheless, the reason for the existence of the OXPHOS supercomplexes and their functional role remains an enigma. Several hypotheses have been proposed for the existence of these supercomplex supercomplexes. A commonly-held view asserts that they enhance catalysis by substrate channeling. However, this - and other views - has been challenged based on structural and biophysical information. Hence, new ideas, concepts, and frameworks are needed. Here, a new model of energy transfer in OXPHOS is developed on the basis of biochemical data on the pure competitive inhibition of anionic substrates like succinate by the classical anionic uncouplers of OXPHOS (2,4-dinitrophenol, carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone, and dicoumarol), and pharmacological data on the unique site-selective, energy-linked inhibition of energy conservation pathways in mitochondria induced by the guanidine derivatives. It is further found that uncouplers themselves are site-specific and exhibit differential selectivity and efficacy in reversing the inhibition caused by the Site 1/Complex I or Site 2/Complexes II-III-selective guanidine derivatives. These results lead to new vistas and sufficient complexity in the network of energy conservation pathways in the mitochondrial respiratory chain that necessitate discrete points of interaction with two classes of guanidine derivatives and uncoupling agents and thereby separate and distinct energy transfer pathways between Site 1 and Site 2 and the intermediate that energizes adenosine triphosphate (ATP) synthesis by Complex V. Interpretation based on Mitchell\'s single-ion chemiosmotic theory that postulates only a single energy pool is inadequate to rationalize the data and account for the required complexity. The above results and available information are shown to be explained by Nath\'s two-ion theory of energy coupling and ATP synthesis, involving coupled movement of succinate anions and protons, along with the requirement postulated by the theory for maintenance of homeostasis and ion translocation across the energy-transducing membrane of both succinate monoanions and succinate dianions by Complexes I-V in the OXPHOS supercomplexes. The new model of energy transfer in mitochondria is mapped onto the solved structures of the supercomplexes and integrated into a consistent model with the three-dimensional electron microscope computer tomography visualization of the internal structure of the cristae membranes in mammalian mitochondria. The model also offers valuable insights into diseased states induced in type 2 diabetes and especially in Alzheimer\'s and other neurodegenerative diseases that involve mitochondrial dysfunction.
摘要：
根据电子低温显微镜的最新进展进行结构测定，现在已经确定，氧化磷酸化（OXPHOS）中的呼吸复合物I-IV在呼吸体中被组织成超复合物。尽管如此，OXPHOS超复合物存在的原因及其功能作用仍然是一个谜。对于这些超复合物的存在，已经提出了几种假设。普遍持有的观点认为，它们通过底物通道增强催化作用。然而,这种观点和其他观点受到了基于结构和生物物理信息的挑战。因此，新的想法,概念,需要框架。这里,根据生化数据，建立了OXPHOS中能量转移的新模型，该数据是通过OXPHOS的经典阴离子解偶联剂（2,4-二硝基苯酚，羰基氰4-(三氟甲氧基)苯腙，和双香豆酚)，和独特的位点选择性的药理学数据，胍衍生物诱导的线粒体能量守恒途径的能量相关抑制。进一步发现,解偶联剂本身是位点特异性的,并且在逆转由位点1/复合物I或位点2/复合物II-III选择性胍衍生物引起的抑制方面表现出不同的选择性和效力。这些结果导致了线粒体呼吸链中能量守恒途径网络的新前景和足够的复杂性，这需要与两类胍衍生物和解偶联剂相互作用的离散点，从而在站点1和站点2之间分离和不同的能量转移途径，并通过ComplexV激发三磷酸腺苷（ATP）合成的中间体。基于Mitchell的单离子化学渗透理论的解释，假设仅有一个单一的能量库的合理性数据是不够的。上述结果和可用的信息被证明是由Nath的能量耦合和ATP合成的双离子理论解释的，涉及琥珀酸根阴离子和质子的耦合运动，以及OXPHOS超复合物中配合物I-V的琥珀酸单阴离子和琥珀酸二阴离子在能量转换膜上维持稳态和离子转运的理论所提出的要求。线粒体中能量转移的新模型被映射到超复合物的求解结构上，并与哺乳动物线粒体cr膜内部结构的三维电子显微镜计算机断层摄影可视化结合到一致的模型中。该模型还提供了对2型糖尿病，尤其是阿尔茨海默病和其他涉及线粒体功能障碍的神经退行性疾病诱导的疾病状态的有价值的见解。
