期刊
PEDIATRIC RESEARCH
卷 83, 期 2, 页码 491-497出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/pr.2017.277
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资金
- NIH [NS-100850]
- MRC [MR/L007339/1, HL-071158]
- American Heart Association pre-doctoral fellowship [17PRE33410360]
- Medical Research Council [MR/L007339/1] Funding Source: researchfish
- MRC [MR/L007339/1] Funding Source: UKRI
BACKGROUND: Reverse electron transport (RET) driven by the oxidation of succinate has been proposed as the mechanism of accelerated production of reactive oxygen species (ROS) in post-ischemic mitochondria. However, it remains unclear whether upon reperfusion, mitochondria preferentially oxidase succinate. METHODS: Neonatal mice were subjected to Rice-Vannucci model of hypoxic-ischemic brain injury (HI) followed by assessment of Krebs cycle metabolites, mitochondrial substrate preference, and H2O2 generation rate in the ischemic brain. RESULTS: While brain mitochondria from control mice exhibited a rotenone-sensitive complex-I-dependent respiration, HI-brain mitochondria, at the initiation of reperfusion, demonstrated complex-II-dependent respiration, as rotenone minimally affected, but inhibition of complex-II ceased respiration. This was associated with a 30-fold increase of cerebral succinate concentration and significantly elevated H2O2 emission rate in HI-mice compared to controls. At 60 min of reperfusion, cerebral succinate content and the mitochondrial response to rotenone did not differ from that in controls. CONCLUSION: These data are the first ex vivo evidence, that at the initiation of reperfusion, brain mitochondria transiently shift their metabolism from complex-I-dependent oxidation of NADH toward complex II-linked oxidation of succinate. Our study provides a critical piece of support for existence of the RET-dependent mechanism of elevated ROS production in reperfusion.
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