Ischaemia-reperfusion (IR) injury occurs when blood supply to an organ is disrupted and then restored, and underlies many disorders, notably heart attack and stroke. While reperfusion of ischaemic tissue is essential for survival, it also initiates oxidative damage, cell death, and aberrant immune responses through generation of mitochondrial reactive oxygen species (ROS)1-5. Although mitochondrial ROS production in IR is established, it has generally been considered a non-specific response to reperfusion1,3. Here, we developed a comparative in vivo metabolomic analysis and unexpectedly identified widely conserved metabolic pathways responsible for mitochondrial ROS production during IR. We showed that selective accumulation of the citric acid cycle (CAC) intermediate succinate is a universal metabolic signature of ischaemia in a range of tissues and is responsible for mitochondrial ROS production during reperfusion. Ischaemic succinate accumulation arises from reversal of succinate dehydrogenase (SDH), which in turn is driven by fumarate overflow from purine nucleotide breakdown and partial reversal of the malate/aspartate shuttle. Upon reperfusion, the accumulated succinate is rapidly re-oxidised by SDH, driving extensive ROS generation by reverse electron transport (RET) at mitochondrial complex I. Decreasing ischaemic succinate accumulation by pharmacological inhibition is sufficient to ameliorate in vivo IR injury in murine models of heart attack and stroke. Thus, we have identified a conserved metabolic response of tissues to ischaemia and reperfusion that unifies many hitherto unconnected aspects of IR injury. Furthermore, these findings reveal a novel pathway for metabolic control of ROS production in vivo, while demonstrating that inhibition of ischaemic succinate accumulation and its oxidation upon subsequent reperfusion is a potential therapeutic target to decrease IR injury in a range of pathologies.

Transient or permanent interruption of cerebral blood flow by occlusion of a cerebral artery gives rise to an ischaemic stroke leading to irreversible damage or dysfunction to the cells within the affected tissue along with permanent or reversible neurological deficit. Extensive research has identified excitotoxicity, oxidative stress, inflammation and cell death as key contributory pathways underlying lesion progression. The cornerstone of treatment for acute ischaemic stroke remains reperfusion therapy with recombinant tissue plasminogen activator (rt-PA). The downstream sequelae of events resulting from spontaneous or pharmacological reperfusion lead to an imbalance in the production of harmful reactive oxygen species (ROS) over endogenous anti-oxidant protection strategies. As such, anti-oxidant therapy has long been investigated as a means to reduce the extent of injury resulting from ischaemic stroke with varying degrees of success. Here we discuss the production and source of these ROS and the various strategies employed to modulate levels. These strategies broadly attempt to inhibit ROS production or increase scavenging or degradation of ROS. While early clinical studies have failed to translate success from bench to bedside, the combination of anti-oxidants with existing thrombolytics or novel neuroprotectants may represent an avenue worthy of clinical investigation. Clearly, there is a pressing need to identify new therapeutic alternatives for the vast majority of patients who are not eligible to receive rt-PA for this debilitating and devastating disease.

Māori women experience an age-adjusted risk of death from breast cancer, which is more than twice that for NZ European women. Equity-focussed improvements in health care, including increasing mammographic screening coverage and providing equitable quality and timely cancer care, may improve the survival disparity between Māori and NZ European women.

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BackgroundIndigenous Māori women experience a 60% higher breast cancer mortality rate compared with European women in New Zealand. We explored the impact of differences in rates of screen detected breast cancer on inequities in cancer stage at diagnosis and survival between Māori and NZ European women.MethodsAll primary breast cancers diagnosed in screening age women (as defined by the New Zealand National Breast Cancer Screening Programme) during 1999–2012 in the Waikato area (n = 1846) were identified from the Waikato Breast Cancer Register and the National Screening Database. Stage at diagnosis and survival were compared for screen detected (n = 1106) and non-screen detected (n = 740) breast cancer by ethnicity and socioeconomic status.ResultsIndigenous Māori women were significantly more likely to be diagnosed with more advanced cancer compared with NZ European women (OR = 1.51), and approximately a half of this difference was explained by lower rate of screen detected cancer for Māori women. For non-screen detected cancer, Māori had significantly lower 10-year breast cancer survival compared with NZ European (46.5% vs. 73.2%) as did most deprived compared with most affluent socioeconomic quintiles (64.8% vs. 81.1%). No significant survival differences were observed for screen detected cancer by ethnicity or socioeconomic deprivation.ConclusionsThe lower rate of screen detected breast cancer appears to be a key contributor towards the higher rate of advanced cancer at diagnosis and lower breast cancer survival for Māori compared with NZ European women. Among women with screen-detected breast cancer, Māori women do just as well as NZ European women, demonstrating the success of breast screening for Māori women who are able to access screening. Increasing breast cancer screening rates has the potential to improve survival for Māori women and reduce breast cancer survival inequity between Māori and NZ European women.