Department of Biochemistry, University of Bologna, Bologna, Italy.
Adv Exp Med Biol. 2012;748:107-44. doi: 10.1007/978-1-4614-3573-0_5.
Recent experimental evidence has replaced the random diffusion model of electron transfer with a model of supramolecular organisation based on specific interactions between individual respiratory complexes. These supercomplexes are detected by blue-native electrophoresis and are found to be functionally relevant by flux control analysis; moreover, they have been isolated and characterised by single-particle electron microscopy. The supramolecular association of individual complexes strongly depends on membrane lipid amount and composition and is affected by lipid peroxidation; it also seems to be modulated by membrane potential and protein phosphorylation. Supercomplex association confers several new properties with respect to the non-associated respiratory complexes to the respiratory chain: the most obvious is substrate channelling, specifically addressing Coenzyme Q and cytochrome c to interact directly with the partner enzymes without the need of a less efficient random diffusion step; in addition, supramolecular association may provide a further rate advantage by conferring long-range conformational changes to the individual complexes. Additional properties are stabilisation of Complex I, as evidenced by the destabilising effect on Complex I of mutations in either Complex III or Complex IV, and prevention of excessive generation of reactive oxygen species. On the basis of the properties described above, we hypothesise that an oxidative stress acts primarily by disassembling supercomplex associations thereby establishing a vicious circle of oxidative stress and energy failure, ultimately leading to cell damage and disease. We provide evidence that in physiological ageing and in some disease states, characterised by oxidative stress and mitochondrial damage, such as heart failure, neurodegenerative disorders and cancer, a loss of supercomplex association occurs, in line with our working hypothesis.
最近的实验证据已经将电子转移的随机扩散模型替换为基于单个呼吸复合物之间特定相互作用的超分子组织模型。这些超复合物通过蓝色非变性电泳检测，并通过通量控制分析发现它们具有功能相关性；此外，它们已经通过单颗粒电子显微镜进行了分离和表征。单个复合物的超分子缔合强烈依赖于膜脂质的数量和组成，并受脂质过氧化的影响；它似乎也受到膜电位和蛋白质磷酸化的调节。超复合物的缔合相对于非缔合的呼吸复合物赋予呼吸链几个新的性质：最明显的是底物通道化，具体地说，将辅酶 Q 和细胞色素 c 直接导向与之相互作用的伴侣酶，而不需要效率较低的随机扩散步骤；此外，超分子缔合可能通过赋予单个复合物长程构象变化来提供进一步的速率优势。其他性质是稳定复合物 I，这可以从复合物 III 或复合物 IV 中的突变对复合物 I 的不稳定作用中得到证明，并且可以防止活性氧物质的过度产生。基于上述性质，我们假设氧化应激主要通过拆散超复合物的缔合来起作用，从而建立氧化应激和能量衰竭的恶性循环，最终导致细胞损伤和疾病。我们提供的证据表明，在生理衰老和某些疾病状态下，如心力衰竭、神经退行性疾病和癌症，氧化应激和线粒体损伤会导致超复合物的缔合丧失，这与我们的工作假说一致。
