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.

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Purpose Approximately 150 million individuals face catastrophic expenditure each year from medical costs alone, and many more from the nonmedical costs of accessing care. The proportion of this expenditure arising from surgical conditions is unknown. Because World Bank has proposed eliminating medical impoverishment by 2030, the impact of surgical conditions on financial catastrophe must be quantified so that any financial risk protection mechanisms can appropriately incorporate surgery. Methods To determine the global incidence of catastrophic expenditure due to surgery, a stochastic model was built. The income distribution of each country, the probability of requiring surgery, and the medical and nonmedical costs faced for surgery were incorporated. Sensitivity analyses were run to test model robustness. Findings 3.7 billion people risk catastrophic expenditure if they need surgery. Every year, 33 million of them are driven to financial catastrophe from the costs of surgery alone, and 48 million from nonmedical costs, leading to 81 million cases worldwide. The burden of catastrophic expenditure is highest in low- and middle-income countries; within any country, it falls on the poor. Estimates are sensitive to the definition of catastrophic expenditure and the costs of care. The inequitable burden distribution is robust to model assumptions. Interpretation Half the global population is at risk of financial catastrophe from surgery. Annually, 81 million individuals, especially the poor, face catastrophic expenditure due to surgical conditions, of which less than half is attributable to medical costs. These findings highlight the need for financial risk protection for surgery in health system design. Funding Partial funding for Dr. Shrime from NIH/NCI R25CA92203.

Available evidence showed increased risk of poor graft outcome in moderate-severe steatotic livers. A large prospective multi-centred trial will be required to identify the true risks of steatotic livers. Consistent definition of primary non-function/impaired primary function and description of type of steatosis is also required.