Mitochondrial dysfunction and role in spreading depolarization and seizure
- 23 Downloads
The effect of pathological phenomena such as epileptic seizures and spreading depolarization (SD) on mitochondria and the potential feedback of mitochondrial dysfunction into the dynamics of those phenomena are complex and difficult to study experimentally due to the simultaneous changes in many variables governing neuronal behavior. By combining a model that accounts for a wide range of neuronal behaviors including seizures, normoxic SD, and hypoxic SD (HSD), together with a detailed model of mitochondrial function and intracellular Ca2+ dynamics, we investigate mitochondrial dysfunction and its potential role in recovery of the neuron from seizures, HSD, and SD. Our results demonstrate that HSD leads to the collapse of mitochondrial membrane potential and cellular ATP levels that recover only when normal oxygen supply is restored. Mitochondrial organic phosphate and pH gradients determine the strength of the depolarization block during HSD and SD, how quickly the cell enters the depolarization block when the oxygen supply is disrupted or potassium in the bath solution is raised beyond the physiological value, and how fast the cell recovers from SD and HSD when normal potassium concentration and oxygen supply are restored. Although not as dramatic as phosphate and pH gradients, mitochondrial Ca2+ uptake has a similar effect on neuronal behavior during these conditions.
KeywordsSpreading depolarization Seizures Mitochondrial dysfunction Ion concentrations Volume dynamics Hypoxia
This study was supported by a startup grant from Collage of Arts and Sciences awarded to Ghanim Ullah.
Compliance with Ethical Standards
Conflict of interests
The authors declare that they have no conflict of interest.
- Avoli, M., Drapeau, C., Louvel, J., Pumain, R., Olivier, A., Villemure, J.G. (1991). Epileptiform activity induced by low extracellular magnesium in the human cortex maintained in vitro. Annals of Neurology:, Official Journal of the American Neurological Association and the Child Neurology Society, 30(4), 589–596.CrossRefGoogle Scholar
- Bahari, F., Ssentongo, P., Liu, J., Kimbugwe, J., Schiff, S.J., Gluckman, B.J. (2018). Spreading depression and seizure unification experimentally observed in epilepsy. bioRxiv p 455519.Google Scholar
- Cohen, P., Wollman, H., Alexander, S., Chase, P., Behar, M. (1964). Cerebral carbohydrate metabolism in man during halothane anesthesiaeffects of paco2 on some aspects of carbohydrate utilization. Anesthesiology:, The Journal of the American Society of Anesthesiologists, 25(2), 185–191.CrossRefGoogle Scholar
- Cressman, J.R., Ullah, G., Ziburkus, J., Schiff, S.J., Barreto, E. (2009). The influence of sodium and potassium dynamics on excitability, seizures, and the stability of persistent states: i. single neuron dynamics. Journal of Computational Neuroscience, 26(2), 159–170.CrossRefPubMedPubMedCentralGoogle Scholar
- Dreier, J.P., Körner, K., Ebert, N., Görner, A., Rubin, I., Back, T., Lindauer, U., Wolf, T., Villringer, A., Einhäupl, K.M., et al. (1998). Nitric oxide scavenging by hemoglobin or nitric oxide synthase inhibition by N-nitro-L-arginine induces cortical spreading ischemia when k + is increased in the subarachnoid space. Journal of Cerebral Blood Flow & Metabolism, 18(9), 978–990.CrossRefGoogle Scholar
- Dreier, J.P., Major, S., Pannek, H.W., Woitzik, J., Scheel, M., Wiesenthal, D., Martus, P., Winkler, M.K., Hartings, J.A., Fabricius, M., et al. (2011). Spreading convulsions, spreading depolarization and epileptogenesis in human cerebral cortex. Brain: A Journal of Neurology, 135(1), 259–275.CrossRefGoogle Scholar
- Dreier, J.P., Fabricius, M., Ayata, C., Sakowitz, O.W., William Shuttleworth, C., Dohmen, C., Graf, R., Vajkoczy, P., Helbok, R., Suzuki, M., et al. (2017). Recording, analysis, and interpretation of spreading depolarizations in neurointensive care: Review and recommendations of the cosbid research group. Journal of Cerebral Blood Flow & Metabolism, 37(5), 1595–1625.CrossRefGoogle Scholar
- Fabricius, M., Fuhr, S., Willumsen, L., Dreier, J.P., Bhatia, R., Boutelle, M.G., Hartings, J.A., Bullock, R., Strong, A.J., Lauritzen, M. (2008). Association of seizures with cortical spreading depression and peri-infarct depolarisations in the acutely injured human brain. Clinical Neurophysiology, 119(9), 1973–1984.CrossRefPubMedPubMedCentralGoogle Scholar
- Gabriel, S., Njunting, M., Pomper, J.K., Merschhemke, M., Sanabria, E.R., Eilers, A., Kivi, A., Zeller, M., Meencke, H.J., Cavalheiro, E.A., et al. (2004). Stimulus and potassium-induced epileptiform activity in the human dentate gyrus from patients with and without hippocampal sclerosis. Journal of Neuroscience, 24(46), 10416–10430.CrossRefPubMedGoogle Scholar
- Galeffi, F., Somjen, G.G., Foster, K.A., Turner, D.A. (2011). Simultaneous monitoring of tissue po2 and nadh fluorescence during synaptic stimulation and spreading depression reveals a transient dissociation between oxygen utilization and mitochondrial redox state in rat hippocampal slices. Journal of Cerebral Blood Flow & Metabolism, 31 (2), 626–639.CrossRefGoogle Scholar
- Hansen, A. (1984). The role of spreading depression in acute brain disorders. Anais da Academia Brasileira de Ci?ncias, 56, 457–479.Google Scholar
- Hartings, J.A., Shuttleworth, C.W., Kirov, S.A., Ayata, C., Hinzman, J.M., Foreman, B., Andrew, R.D., Boutelle, M.G., Brennan, K., Carlson, A.P., et al. (2017). The continuum of spreading depolarizations in acute cortical lesion development: examining leão?s legacy. Journal of Cerebral Blood Flow & Metabolism, 37(5), 1571–1594.CrossRefGoogle Scholar
- Hawrysh, P.J., & Buck, L.T. (2019). Mitochondrial matrix ph acidifies during anoxia and is maintained by the f1f0-atp ase in anoxia-tolerant painted turtle cortical neurons. FEBS Open Bio pp. https://doi.org/10.1002/2211--5463.12612.
- Jitschin, R., Hofmann, A.D., Bruns, H., Gießl, A., Bricks, J., Berger, J., Saul, D., Eckart, M.J., Mackensen, A., Mougiakakos, D. (2014). Mitochondrial metabolism contributes to oxidative stress and reveals therapeutic targets in chronic lymphocytic leukemia. Blood, 123(17), 2663–2672.CrossRefPubMedGoogle Scholar
- Köhling, R., Koch, U., Hagemann, G., Redecker, C., Straub, H., Speckmann, E.J. (2003). Differential sensitivity to induction of spreading depression by partial disinhibition in chronically epileptic human and rat as compared to native rat neocortical tissue. Brain Research, 975(1-2), 129–134.CrossRefPubMedGoogle Scholar
- Lauritzen, M., Dreier, J.P., Fabricius, M., Hartings, J.A., Graf, R., Strong, A.J. (2011). Clinical relevance of cortical spreading depression in neurological disorders: migraine, malignant stroke, subarachnoid and intracranial hemorrhage, and traumatic brain injury. Journal of Cerebral Blood Flow & Metabolism, 31(1), 17–35.CrossRefGoogle Scholar
- Lee, B.H., Seo, H.W., Yi, K.Y., Lee, S., Lee, S., Yoo, S.E. (2005). Effects of kr-32570, a new na+/h+ exchanger inhibitor, on functional and metabolic impairments produced by global ischemia and reperfusion in the perfused rat heart. European Journal of Pharmacology, 511(2-3), 175–182.CrossRefPubMedGoogle Scholar
- Murphy, M.P., & Hartley, R.C. (2018). Mitochondria as a therapeutic target for common pathologies. Nature Reviews Drug Discovery.Google Scholar
- Østby, I., Øyehaug, L., Einevoll, G.T., Nagelhus, E.A., Plahte, E., Zeuthen, T., Lloyd, C.M., Ottersen, O.P., Omholt, S.W. (2009). Astrocytic mechanisms explaining neural-activity-induced shrinkage of extraneuronal space. PLos Computational Biology, 5(1), e1000272.CrossRefPubMedPubMedCentralGoogle Scholar
- Pomper, J.K., Haack, S., Petzold, G.C., Buchheim, K., Gabriel, S., Hoffmann, U., Heinemann, U. (2006). Repetitive spreading depression-like events result in cell damage in juvenile hippocampal slice cultures maintained in normoxia. Journal of Neurophysiology.Google Scholar
- Schechter, M., Sonn, J., Mayevsky, A. (2009). Brain oxygen balance under various experimental pathophysiologycal conditions. In Oxygen Transport to Tissue (pp. 293–299). Berlin: Springer.Google Scholar
- Somjen, G.G. (2004). Ions in the brain New york: Oxford UP.Google Scholar