Selective S-nitrosation of mitochondrial complex I by MitoSNO as a new therapy for cardiac ischaemia-reperfusion injury

缺血再灌注（IR）损伤是许多临床重要疾病的基础，如心脏病发作和中风。当器官的血液供应被中断时，例如被血凝块中断，就会发生缺血。如果血液供应恢复，组织可以恢复。然而，用含氧血液对缺血器官进行再灌注会导致广泛的组织损伤，这会影响患者的长期预后。这种损伤主要是由再灌注过程中线粒体产生的破坏性自由基引起的，导致细胞死亡。我们已经开发了一种新的靶向药物MitoSNO，可以防止IR损伤期间线粒体产生自由基。MitoSNO包含亲脂性阳离子，其在缺血器官的再灌注期间在其静脉内注射后立即驱动其快速且广泛地摄取到心脏内的线粒体中。在线粒体内，MitoSNO选择性地将一氧化氮部分转移到呼吸复合物I上的特定半胱氨酸上，从而防止再灌注期间通常发生的线粒体自由基产生。这种修饰在5-10分钟后逆转，使线粒体恢复完全活性。啮齿动物研究表明，MitoSNO在临床相关的体内模型中预防心脏IR损伤，从而大大增强心脏功能的长期恢复。MitoSNO是独特的，因为没有其他保护性疗法可以应用于再灌注时的器官以阻断线粒体自由基的产生。在这项研究中，将评估MitoSNO，以确定它是否也能保护猪免受IR损伤，为首次人体I期研究做准备。由于在其他情况下发现了类似的IR损伤，例如心脏病发作和器官移植，MitoSNO也可以证明是一系列适应症的有用治疗剂。

Ischaemia-reperfusion (IR) injury underlies many clinically important conditions, such as heart attack and stroke. Ischaemia occurs when the blood supply to an organ is interrupted, for example by a blood clot. If the blood supply is restored the tissue can recover. However, reperfusion of the ischaemic organ with oxygenated blood leads to extensive tissue damage that worsens the long-term prognosis for the patient. This injury is initiated largely by the production of damaging free radicals from mitochondria during reperfusion that leads to cell death. We have developed a novel mitochondria-targeted drug called MitoSNO that prevents free radical production from mitochondria during IR injury. MitoSNO comprises a lipophilic cation that drives its rapid and extensive uptake into mitochondria within the heart immediately following its intravenous injection during reperfusion of the ischaemic organ. Within mitochondria MitoSNO selectively transfers a nitric oxide moiety onto a particular cysteine on respiratory complex I, thereby preventing the mitochondrial free radical production that normally occurs during reperfusion. This modification is reversed after 5-10 mins allowing the mitochondria to return to full activity. Rodent studies have shown that MitoSNO prevents cardiac IR injury in clinically relevant in vivo models, thereby greatly enhancing the long-term recovery of heart function. MitoSNO is unique as no other protective therapies can be applied to organs at reperfusion to block mitochondrial free radical production. In this study MitoSNO will be assessed to see if it is also protective against IR injury in pigs in preparation for a first-in-man Phase I study. As similar IR injury is found in other situations, such as heart attack and organ transplantation, MitoSNO may also prove a useful therapeutic for a range of indications.