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Succinate strikes

Nature volume 515, pages 350351 (20 November 2014) | Download Citation

The high levels of tissue-damaging reactive oxygen species that arise during a stroke or heart attack have been shown to be generated through the accumulation of the metabolic intermediate succinate. See Letter p.431

When a stroke or a heart attack strikes, the tissue injury that occurs can be devastating. This damage to the brain or heart is a result of an initial starving of oxygen owing to blocked blood flow, followed by reoxygenation once blood flow is restored. Ischaemia reperfusion (IR) injury, as it is called, is a major health burden, and there are very few options to prevent it. On page 431 of this issue, Chouchani and colleagues1 present a finding that might inspire a new therapeutic approach. They reveal that succinate, an intermediate molecule normally formed during cellular respiration, is consistently elevated in ischaemic tissues, and that preventing this elevation is remarkably protective against IR injury in mouse models of stroke and heart attack. These findings add to those from other studies implicating succinate as an injurious metabolite, the limitation of which might have clinical utility2,3.

The study began with an investigation into why tissue-damaging molecules called reactive oxygen species (ROS) are produced at abnormally high levels during IR injury4. ROS are formed as a by-product of cellular respiration — the series of reduction and oxidation reactions, occurring in organelles called mitochondria, that generates energy from the breakdown of nutrients. The authors proposed that any changes in metabolite levels during ischaemia and reperfusion might predict the source of excessive ROS. They blocked blood flow to four tissues (brain, kidney, heart and liver) in mice, and found succinate to be elevated in all four, by as much as 19-fold, over ischaemic periods of 45 minutes. In fact, succinate was the only intermediate of mitochondrial metabolism found at altered levels in all the ischaemic tissues.

If succinate were fuelling the ROS accumulation, Chouchani et al. predicted that it would be rapidly oxidized during reperfusion, when oxygen is plentiful; indeed, they observed that succinate levels returned to normal after 5 minutes of reperfusion. They then addressed where the succinate might be coming from, and tested an earlier speculation5 that the enzyme succinate dehydrogenase (SDH), which breaks down succinate during normal oxygen-consuming cellular respiration, might act in reverse under anaerobic conditions. This also proved to be the case — the researchers found that succinate is generated from its usual downstream metabolite fumarate in the ischaemic tissues through the action of SDH, and that treatment of mice with a form of malonate, an SDH inhibitor, decreased succinate accumulation during ischaemia and reduced the extent of tissue damage in models of both heart and brain IR injury. Furthermore, in the brain model, malonate treatment prevented the decline in neurological function and sensorimotor function associated with stroke.

The authors went on to identify that excessive ROS production occurs when SDH drives reverse electron transport through mitochondrial complex I, the first enzyme complex in the cellular-respiration chain (Fig. 1). This reverse electron transport occurs because, on reperfusion, the succinate that has accumulated is rapidly oxidized, leading to over-reduction of the cellular pool of coenzyme Q molecules, which are crucial electron carriers during respiration. The over-reduction drives electrons back through complex I, generating ROS in the process. The researchers also show that blocking electron flow through complex I using the chemical compounds rotenone or mitochondria-targeted S-nitrosothiol6 inhibits the increase in ROS in tissues undergoing reperfusion after ischaemia.

Figure 1: Succinate in inflammation and infarct.
Figure 1

Chouchani et al.1 show that the metabolic intermediate succinate is markedly elevated during ischaemia — oxygen deprivation to a tissue as a result of blocked blood supply. This accumulation occurs through the reverse activity of the enzyme succinate dehydrogenase (SDH). On blood reperfusion, the succinate is oxidized, leading to reverse electron transport through complex 1 (a multiprotein enzyme complex), which generates reactive oxygen species (ROS) — molecules that mediate the infarct (damaged tissue) seen in strokes and heart attacks and that promote inflammation. Succinate has also been implicated in inflammation driven by macrophage cells that are activated when the receptor TLR4 is bound by the bacterial component lipopolysaccharide (LPS)2 or, perhaps, by products of ischaemic tissue10. In this case, the succinate is generated from the metabolism of glutamine, and leads to activation of the transcription factor HIF-1α and expression of genes encoding pro-inflammatory proteins.

These findings join those of several other studies pointing to succinate as an inducer of inflammation2,3,7,8,9. Most notable among these is the finding2 that macrophage cells of the immune system are induced to produce succinate following activation through Toll-like receptor 4 (TLR4), which recognizes lipopolysaccharide, a component of the cell walls of some bacteria (Fig. 1). In that situation, the succinate is generated from the amino acid glutamine and acts to stabilize the transcription factor HIF-1α, which in turn leads to an increase in activity of HIF-1α-dependent genes, one of which encodes the pro-inflammatory molecule IL-1β (ref. 2). Of direct relevance to the current study are observations that implicate TLR4 (and TLR2) in IR injury in the heart10,11. It is possible that macrophage TLRs are bound by products of damaged tissue during ischaemia, activating the cells to produce succinate and thus contributing to IR injury.

Succinate is also elevated in other inflammatory conditions, including colitis6 and rheumatoid arthritis7, and it is possible that succinate generates ROS in those conditions through complex I, as shown by Chouchani and colleagues. And binding of succinate to a receptor called SUCNR1, which is expressed by dendritic cells of the immune system, has been shown to enhance the production of pro-inflammatory molecules by these cells when they are activated by TLR binding.

Chouchani and co-workers' study should therefore stimulate further analysis not only of the importance of succinate as a mediator of IR injury, but also of the molecule's broader role in inflammatory conditions and disease states involving mitochondrial ROS. Preventing succinate accumulation could bring benefits by limiting inflammation in conditions such as sepsis or rheumatoid arthritis, and may provide a new approach for limiting the damage caused by heart attack or stroke. Ultimately, the targeting of the events described here could result in much-needed therapies for patients for whom there are currently limited options.

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  1. Luke A. J. O'Neill is in the School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.

    • Luke A. J. O'Neill

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Correspondence to Luke A. J. O'Neill.

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