Abstract
Isolated exposure to intermittent hypoxia and permissive hypercapnia activates signaling mechanisms that induce ultrastructural changes in mitochondria and endoplasmic reticulum, accompanied by the development of maximal ischemic tolerance in neurons under the combined influence of these factors. However, there are a lack of data on the combined impact of these factors on the ultrastructure of neuronal organelles. The present study aims to comparatively assess the ultrastructural changes in neurons following isolated and combined exposure to hypoxia and hypercapnia, as well as to correlate these changes with the neuroprotective potential previously observed for these factors. Following a 15-session course of 30-min exposures to permissive hypercapnia (PCO2 ≈ 50 mmHg) and/or normobaric hypoxia (PO2 ≈ 150 mmHg), morphometric assessment was conducted to evaluate the extent of ultrastructural changes in hippocampal neurons (mitochondria, perinuclear space, and granular endoplasmic reticulum). It was found that in hippocampal neurons from the CA1 region, permissive hypercapnia resulted in increased mitochondrial size, expansion of membranous compartments of the granular endoplasmic reticulum, and perinuclear space. Normobaric hypoxia affected only mitochondrial size, while hypercapnic hypoxia specifically widened the perinuclear space. These ultrastructural changes objectively reflect varying degrees of the influence of hypoxia and hypercapnia on organelles responsible for energy metabolism, anti-apoptotic, and synthetic functions of neurons. This confirms the effect of potentiation of their neuroprotective effects under combined exposure and highlights the dominant role of the hypercapnic component in this mechanism.
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References
Bento LM, Fagian MM, Vercesi AE, Gontijo JA (2007) Effects of NH4Cl-induced systemic metabolic acidosis on kidney mitochondrial coupling and calcium transport in rats. Nephrol Dial Transplant 22(10):2817–2823. https://doi.org/10.1093/ndt/gfm306
Boito CA, Fanin M, Gavassini BF, Cenacchi G, Angelini C, Pegoraro E (2007) Biochemical and ultrastructural evidence of endoplasmic reticulum stress in LGMD2I. Virchows Arch 451(6):1047–1055. https://doi.org/10.1007/s00428-007-0515-3
Chuang IC, Dong HP, Yang RC, Wang TH, Tsai JH, Yang PH, Huang MS (2010) Effect of carbon dioxide on pulmonary vascular tone at various pulmonary arterial pressure levels induced by endothelin-1. Lung 188:199–207
Dell RB, Holleran S, Ramakrishnan R (2002) Sample size determination. ILAR J 43:207–213
Dittmann K, Mayer C, Rodemann HP (2010) Nuclear EGFR as novel therapeutic target: insights into nuclear translocation and function. Strahlenther Onkol 186(1):1–6. https://doi.org/10.1007/s00066-009-2026-4
Jung ME, Mallet RT (2018) Intermittent hypoxia training: Powerful, non-invasive cerebroprotection against ethanol withdrawal excitotoxicity. Respir Physiol Neurobiol 256:67–78
Kang JJ, Fung ML, Zhang K, Lam CS, Wu SX, Huang XF, Yang SJ, Wong-Riley MTT, Liu YY (2020) Chronic intermittent hypoxia alters the dendritic mitochondrial structure and activity in the pre-Bötzinger complex of rats. FASEB J 34(11):14588–14601. https://doi.org/10.1096/fj.201902141R
Kitamura M (2008) Endoplasmic reticulum stress and unfolded protein response in renal pathophysiology: Janus faces. Am J Physiol Renal Physiol 295(2):F323–F334
Kulikov VP, Tregub PP, Bespalov AG, Vvedenskiy AJ (2013) Comparative efficacy of hypoxia, hypercapnia and hypercapnic hypoxia increases body resistance to acute hypoxia in rats. Patol Fiziol Eksp Ter 3:59–61
Kulikov VP, Motin Yu G, Tregub PP, Kovzelev PD, Shoshin KA, Zinchenko EK, Chernetsky AE (2018) Combined hypercapnia and hypoxia lead to the acidosis and increase the amount HIF-1a in rat hippocampus. IM Sechenov Russian J Physiol 104(11):1347–1355
Lavoie C, Paiement J (2008) Topology of molecular machines of the endoplasmic reticulum: a compilation of proteomics and cytological data. Histochem Cell Biol 129(2):117–128. https://doi.org/10.1007/s00418-007-0370-y
Lukyanova L, Germanova E, Khmil N et al (2021) Signaling role of mitochondrial enzymes and ultrastructure in the formation of molecular mechanisms of adaptation to hypoxia. Int J Mol Sci 22(16):8636
Motin YG, Lepilov AV, Bgatova NP, Zharikov AY, Motina NV, Lapii GA, Lushnikova EL, Nepomnyashchikh LM (2016) Development of endoplasmic reticulum stress during experimental oxalate nephrolithiasis. Bull Exp Biol Med 160(3):381–385. https://doi.org/10.1007/s10517-016-3176-x
Obrenovitch TP (2008) Molecular physiology of preconditioning-induced brain tolerance to ischemia. Physiol Rev 88:211–247. https://doi.org/10.1152/physrev.00039.2006
Pruimboom L, Muskiet FAJ (2018) Intermittent living: the use of ancient challenges as a vaccine against the deleterious effects of modern life—a hypothesis. Med Hypotheses 120:28–42
Rybnikova E, Samoilov M (2015) Current insights into the molecular mechanisms of hypoxic pre- and postconditioning using hypobaric hypoxia. Front Neurosci 9:388
Rybnikova EA, Nalivaeva MY, Zenko NN (2022) Intermittent hypoxic training as an effective tool for increasing the adaptive potential, endurance and working capacity of the brain. Front Neurosci 16:941740
Schuldiner M, Schwappach B (2013) From rags to riches—the history of the endoplasmic reticulum. Biochim Biophys Acta 1833(11):2389–2391. https://doi.org/10.1016/j.bbamcr.2013.03.005
Secondo A, Petrozziello T, Tedeschi V, Boscia F, Pannaccione A, Molinaro P, Annunziato L (2020) Nuclear localization of NCX: role in Ca2+ handling and pathophysiological implications. Cell Calcium 86:102143. https://doi.org/10.1016/j.ceca.2019.102143
Su Y, Ke C, Li C, Huang C, Wan C (2022) Intermittent hypoxia promotes the recovery of motor function in rats with cerebral ischemia by regulating mitochondrial function. Exp Biol Med (Maywood) 247(15):1364–1378. https://doi.org/10.1177/15353702221098962
Tao T, Zhao M, Yang W et al (2014) Neuroprotective effects of therapeutic hypercapnia on spatial memory and sensorimotor impairment via anti-apoptotic mechanisms after focal cerebral ischemia/reperfusion. Neurosci Lett 24(573):1–6
Tregub P, Kulikov V, Bespalov A (2013) Tolerance to acute hypoxia maximally increases in case of joint effect of normobaric hypoxia and permissive hypercapnia in rats. Pathophysiology 20(3):165–170. https://doi.org/10.1016/j.pathophys.2013.09.001
Tregub P, Kulikov V, Motin Y, Bespalov A, Osipov I (2015) Combined exposure to hypercapnia and hypoxia provides its maximum neuroprotective effect during focal ischemic injury in the brain. J Stroke Cerebrovasc Dis 24(2):381–387. https://doi.org/10.1016/j.jstrokecerebrovasdis.2014.09.003
Tregub PP, Kulikov VP, Motin YG, Nagibaeva ME, Zabrodina AS (2016) Stress of the endoplasmic reticulum of neurons in stroke can be maximally limited by combined exposure to hypercapnia and hypoxia. Bull Exp Biol Med 161(4):472–475. https://doi.org/10.1007/s10517-016-3441-z
Tregub PP, Malinovskaya NA, Osipova ED, Morgun AV, Kulikov VP (2023) Permissive hypercapnia and hypercapnic hypoxia inhibit signaling pathways of neuronal apoptosis in ischemic/hypoxic rats. Mol Biol Rep 50(3):2317–2333. https://doi.org/10.1007/s11033-022-08212-4
Voeltz GK, Rolls MM, Rapoport TA (2002) Structural organization of the endoplasmic reticulum. EMBO Rep 3(10):944–950. https://doi.org/10.1093/embo-reports/kvf202
Wu XC, Lai J, Wu XF, Jia ZH, Wei C, Wang HT (2011) Effects of Tongxinluo on neuron ultrastructure and endothelial cell self-repairing ability in hypoxia preconditioning mice. Zhongguo Ying Yong Sheng Li Xue Za Zhi 27(4):396–399 (Chinese)
Yan F, Li J, Chen J, Hu Q, Gu C, Lin W, Chen G (2014) Endoplasmic reticulum stress is associated with neuroprotection against apoptosis via autophagy activation in a rat model of subarachnoid hemorrhage. Neurosci Lett 563:160–165. https://doi.org/10.1016/j.neulet.2014.01.058
Zhao YD, Cheng SY, Ou S, Xiao Z, He WJ, Jian-Cui RHZ (2012) Effect of hypobaric hypoxia on the P2X receptors of pyramidal cells in the immature rat hippocampus CA1 sub-field. Brain Inj 26(3):282–290
Zhong N, Zhang Y, Zhu HF, Zhou ZN (2000) Intermittent hypoxia exposure prevents mtDNA deletion and mitochondrial structure damage produced by ischemia/reperfusion injury. Sheng Li Xue Bao 52(5):375–380
Zhou AM, Li WB, Li QJ, Liu HQ, Feng RF, Zhao HG (2004) A short cerebral ischemic preconditioning upregulates adenosine receptors in the hippocampal CA1 region of rats. Neurosci Res 48:397–404
Zhou Q, Cao B, Niu L et al (2010) Effects of permissive hypercapnia on transient global cerebral ischemia–reperfusion injury in rats. Anesthesiology 112:288–297
Acknowledgements
We wish to thank Prof. Alla Salmina for great help in the work on this study.
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This publication has been supported by RUDN University project № 210500-2-000, «Molecular mechanisms of mast cell participation in the formation of the immune and stromal landscape of a specific tissue microenvironment in normal and pathological conditions (oncogenesis, inflammation, fibrosis) ».
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Conceptualization: PT and VK; Data curation: PT, AC, and II; Formal analysis: PT; Funding acquisition: PT; Investigation: PT, PK, and AC; Methodology: PT, YM, and PK; Project administration: PT and VK; Resources: PT; Software: PT and II; Supervision: PT; Validation: PT, YM, VK, and II; Visualization: PT and YM; Writing of the original draft: PT and VK; Writing, reviewing, & editing of the manuscript: PT and II.
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Tregub, P., Motin, Y., Kulikov, V. et al. Ultrastructural Changes in Hippocampal Region CA1 Neurons After Exposure to Permissive Hypercapnia and/or Normobaric Hypoxia. Cell Mol Neurobiol 43, 4209–4217 (2023). https://doi.org/10.1007/s10571-023-01407-8
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DOI: https://doi.org/10.1007/s10571-023-01407-8