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

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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.