Succinate accumulates during ischemia forcing mitochondrial complex I to operate in reversal, while producing oxidant species during reperfusion

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by José Carlos Toledo

Ischemia-reperfusion (IR) is a process where blood supply (thus oxygen supply) to an organ is interrupted and then restored. While reperfusion is essential for survival, it is accompanied by a burst of mitochondrial generation of redox species and intermediates such as superoxide and hydrogen peroxide. Such species associate with derived ischemic tissue injury, underling disorders such as heart attack and stroke [1]. Nonetheless, IR mitochondrial ROS production has been considered a nonspecific consequence of a dysfunctional interaction of mitochondrial redox chain components with oxygen during reperfusion. Using a comparative Liquid chromatography-mass spectrometry (LC-MS) metabolomic analysis of several mouse organs subjected to IR in vivo, Chouchani et al. [2] found that succinate was the only mitochondrial metabolite that accumulates across all tissues and may be responsible for ROS production during reperfusion. Succinate dehydrogenase (SDH, mitochondrial complex II) normally oxidizes succinate to fumarate, but during ischemia fumarate accumulates, forcing SDH to operate in reversal to produce succinate. Succinate notably causes extensive superoxide production by complex I reverse electron transport in vitro [3], so its accumulation during ischemia is a compelling potential source of mitochondrial ROS. Consistently, the authors show succinate-dependent oxidation of different ROS probes in a primary cardiomyocite model of IR and during murine cardiac IR injury in vivo and that this oxidation is augmented or minimized by interventions that either increase or decrease succinate levels. Furthermore, they show that avoiding succinate accumulation during ischemia or inhibiting SDH or complex I pharmacologically is sufficient to ameliorate IR injury in murine models of heart attack and stroke. Both complex I and complex II normally provide reduced quinones that in turn drive electron transport forward through complex III and complex IV to oxygen at the expense of NADH and succinate, respectively. Chouchani et al. [2] provides evidence to create a model where, in the early stages of reperfusion, SDH rapidly consumes the succinate providing a reduced quinone pool sufficient to maintain conventional electron transport while also driving complex I reverse electron transport. Thus, this study [2] offers compelling evidence for the existence of a single mitochondrial metabolite and a conserved metabolic response of tissues to IR that unify many unconnected aspects of IR injury and offer new avenues for therapeutic interventions.


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    Ischemia and reperfusion-from mechanism to translation.
    Nature Medicine, 17 (11): 1391-401, 2011. | http://dx.doi.org/10.1038/nm.2507
  2. E. T. Chouchani, V. R. Pell, E. Gaude, D. Aksentijevic, S. Y. Sundier, E. L. Robb, A. Logan, S. M. Nadtochiy, E. N. J. Ord, A. C. Smith, F. Eyassu, R. Shirley, C. -H. Hu, A. J. Dare, A. M. James, S. Rogatti, R. C. Hartley, S. Eaton, A. S. H. Costa, P. S. Brookes, S. M. Davidson, M. R. Duchen, K. Saeb-Parsy, M. J. Shattock,  A. J. Robinson, L. M. Work, C. Frezza, T. Krieg, M. P. Murphy.
    Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS.
    Nature, 515 (7527): 431-5, 2014. | http://dx.doi.org/10.1038/nature13909
  3. Z. V. Niatsetskaya, S. A. Sosunov, D. Matsiukevich, I. V. Utkina-Sosunova, V. I. Ratner, A. A. Starkov, V. S. Ten.
    The oxygen free radicals originating from mitochondrial complex I contribute to oxidative brain injury following hypoxia-ischemia in neonatal mice.
    Journal of Neuroscience,  32 (9): 3235-44, 2012. | http://dx.doi.org/10.1523/jneurosci.6303-11.2012

 José Carlos Toledo Jr, PhD.
Professor at Department of Chemistry,
Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto,
University of São Paulo, Brazil

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