Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS.
Level 5 - mechanism / opinion, no new human data
Preclinical animal and metabolomic mechanistic research without human subjects.
PubMed 25383517 · doi:10.1038/nature13909
What was done
The authors conducted comparative in vivo metabolomic profiling across tissues to identify metabolic pathways driving mitochondrial reactive oxygen species (ROS) production during ischaemia-reperfusion. They investigated the biochemical source of metabolite accumulation during ischaemia and tested pharmacological inhibition of this pathway in murine models of myocardial infarction and stroke.
What was found
The abstract provides no numerical data. It reports that succinate accumulates across multiple ischaemic tissues due to reversal of succinate dehydrogenase, driven by fumarate overflow and partial reversal of the malate/aspartate shuttle. On reperfusion, rapid re-oxidation of accumulated succinate drives ROS generation through reverse electron transport at mitochondrial complex I. Pharmacological inhibition of ischaemic succinate accumulation reduced ischaemia-reperfusion injury in murine models of heart attack and stroke.
Why it matters
This study defines succinate accumulation and subsequent oxidation as a central metabolic mechanism causing ROS-mediated tissue damage during reperfusion, offering a potential therapeutic target for ischaemia-reperfusion injury.
Limits
No quantitative data, sample sizes, or specific pharmacological agents and doses are reported in the abstract. The findings are derived entirely from preclinical animal models and mechanistic assays, without evaluation in human clinical trials.