Mitochondrial structure and function in cognitively impaired rats with severe intermittent hypoxia_Chinese Journal of Respiratory and Critical Care Medicine

Authors：

WANG Xiayan ¹ , LING Jizu ² ,  YE Xinhua ³

1. Department of Pediatrics, First Clinical Medical College of Lanzhou University, Lanzhou, Gansu 730000, P. R. China;
2. Department of Pediatrics, First Hospital of Lanzhou University, Lanzhou, Gansu 730000, P. R. China;
3. Department of Child Health Care, First Hospital of Lanzhou University, Lanzhou, Gansu 730000, P. R. China;

Corresponding author：

YE Xinhua, Email: ye_xinhua@126.com

Keywords：

Obstructive sleep apnea-hypopnea syndrome; intermittent hypoxia; cognitive impairment; hippocampus; mitochondria

DOI：

10.7507/1671-6205.202405066

Video：

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Objective To investigate the changes in mitochondrial morphology, structure and function in rats with severe intermittent hypoxia, as well as the effects of intermittent hypoxia and its severity on cognitive function. Methods A total of 18 rats were selected to construct a model of severe intermittent hypoxia, which were divided into a normal control group, an intermittent air control group, and a 5% intermittent hypoxia group for 8 weeks, with 6 rats in each group. The structural and functional changes of mitochondria in the hippocampal CA1 region were observed. A total of 30 rats were randomly divided into 5 groups: a normal control group, an intermittent air control group, a 5% intermittent hypoxia 4-week group, a 5% intermittent hypoxia 6-week group, and a 5% intermittent hypoxia 8-week group, with 6 rats in each group. The cognitive function of the rats in each group was evaluated by Morris water maze experiment. Results In the mitochondria of the hippocampal CA1 region of severely intermittent hypoxic rats, bilayer membranes or multilayer membranes were visible, the mitochondria were swollen, cristae were broken and vacuolated, and their respiratory function was significantly weakened, the membrane permeability was increased, and the membrane potential was reduced. In the Morris water maze, there was no significant difference in swimming speed between the rats. With the prolongation of intermittent hypoxia action time, the latency of finding the hidden platform in each group of rats increased significantly, and the residence time of the target quadrant decreased significantly. Conclusions Mitochondrial structure in the hippocampal CA1 region of the rat brain is destroyed during severe intermittent hypoxia, and dysfunction and cognitive impairment occur. With the prolongation of intermittent hypoxic injury, the degree of cognitive impairment worsens.

Citation： WANG Xiayan, LING Jizu, YE Xinhua. Mitochondrial structure and function in cognitively impaired rats with severe intermittent hypoxia. Chinese Journal of Respiratory and Critical Care Medicine, 2024, 23(10): 727-733. doi: 10.7507/1671-6205.202405066 Copy

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2.	Coimbra-Costa D, Alva N, Duran M, et al. Oxidative stress and apoptosis after acute respiratory hypoxia and reoxygenation in rat brain. Redox Biol, 2017, 12: 216-225.
3.	Polšek D, Bago M, Živaljić M, et al. A novel adjustable automated system for inducing chronic intermittent hypoxia in mice. Sakakibara M, ed. PLoS ONE, 2017, 12(3): e0174896.
4.	Alle H, Roth A, Geiger JRP. Energy-efficient action potentials in hippocampal mossy fibers. Science, 2009, 325(5946): 1405-1408.
5.	Harris JJ, Jolivet R, Attwell D. Synaptic energy use and supply. Neuron, 2012, 75(5): 762-777.
6.	Cobley JN, Fiorello ML, Bailey DM. 13 reasons why the brain is susceptible to oxidative stress. Redox Biol, 2018, 15: 490-503.
7.	Zorov DB, Juhaszova M, Sollott SJ. Mitochondrial ROS-induced ROS release: an update and review. Biochim Biophys Acta, 2006, 1757(5-6): 509-517.
8.	Schon EA, Przedborski S. Mitochondria: The Next (Neurode) Generation. Neuron, 2011, 70(6): 1033-1053.
9.	彭万达, 陈锐, 蒋震, 等. 阻塞性睡眠呼吸暂停低通气综合征患者海马及脑白质病变与认知功能的相关性. 中华医学杂志, 2014, 94(10): 724-728.
10.	Morrell M. Changes in brain morphology associated with obstructive sleep apnea. Sleep Med, 2003, 4(5): 451-454.
11.	Gao H, Han Z, Huang S, et al. Intermittent hypoxia caused cognitive dysfunction relate to miRNAs dysregulation in hippocampus. Behav Brain Res, 2017, 335: 80-87.
12.	Jing F, Qi W, Dan Z, et al. Hippocampal impairments are associated with intermittent hypoxia of obstructive sleep apnea. Chin Med J (Engl), 2012, 125(4): 696-701.
13.	May A, Mehra R. Obstructive sleep apnea: role of intermittent hypoxia and inflammation. Semin Respir Crit Care Med, 2014, 35(05): 531-544.
14.	Wall AM, Corcoran AE, O’Halloran KD, et al. Effects of prolyl-hydroxylase inhibition and chronic intermittent hypoxia on synaptic transmission and plasticity in the rat CA1 and dentate gyrus. Neurobiol Dis, 2014, 62: 8-17.
15.	Chou YT, Zhan G, Zhu Y, et al. C/EBP homologous binding protein (CHOP) underlies neural injury in sleep apnea model. Sleep, 2013, 36(4): 481-492.
16.	Ugale V, Deshmukh R, Lokwani D, et al. GluN2B subunit selective N-methyl-D-aspartate receptor ligands: democratizing recent progress to assist the development of novel neurotherapeutics. Mol Divers, 2023, 28(3): 1765-1792.
17.	Arias-Cavieres A, Khuu MA, Nwakudu CU, et al. A HIF1a-dependent pro-oxidant state disrupts synaptic plasticity and impairs spatial memory in response to intermittent hypoxia. eNeuro, 2020, 7(3): ENEURO.0024-20.2020.
18.	Prabhakar NR, Peng YJ, Nanduri J. Hypoxia-inducible factors and obstructive sleep apnea. J Clin Invest, 2020, 130(10): 5042-5051.
19.	Mironov SL. Complexity of mitochondrial dynamics in neurons and its control by ADP produced during synaptic activity. Int J Biochem Cell Biol, 2009, 41(10): 2005-2014.
20.	Mnatsakanyan N, Jonas EA. The new role of F1Fo ATP synthase in mitochondria-mediated neurodegeneration and neuroprotection. Exp Neurol, 2020, 332: 113400.
21.	Douglas RM, Ryu J, Kanaan A, et al. Neuronal death during combined intermittent hypoxia/hypercapnia is due to mitochondrial dysfunction. Am J Physiol Cell Physiol, 2010, 298(6): C1594-C1602.
22.	Erecińska M, Silver IA. Tissue oxygen tension and brain sensitivity to hypoxia. Respir Physiol, 2001, 128(3): 263-276.
23.	Liochev SI. Reactive oxygen species and the free radical theory of aging. Free Radic Biol Med, 2013, 60: 1-4.
24.	Hunter DR, Haworth RA, Southard JH. Relationship between configuration, function, and permeability in calcium-treated mitochondria. J Biol Chem, 1976, 251(16): 5069-5077.
25.	Kristián T. Metabolic stages, mitochondria and calcium in hypoxic/ischemic brain damage. Cell Calcium, 2004, 36(3-4): 221-233.
26.	Zhou L, Chen P, Peng Y, et al. Role of Oxidative stress in the neurocognitive dysfunction of obstructive sleep apnea syndrome. Oxid Med Cell Longev, 2016, 2016: 1-15.
27.	Aoyama K, Watabe M, Nakaki T. Regulation of neuronal glutathione synthesis. J Pharmacol Sci, 2008, 108(3): 227-238.
28.	Ling J, Yu Q, Li Y, et al. Edaravone improves intermittent hypoxia-induced cognitive impairment and hippocampal damage in rats. Biol Pharm Bull, 2020, 43(8): 1196-1201.

1. Koritala BSC, Lee YY, Gaspar LS, et al. Obstructive sleep apnea in a mouse model is associated with tissue-specific transcriptomic changes in circadian rhythmicity and mean 24-hour gene expression. Hattar S, ed. PLoS Biol, 2023, 21(5): e3002139.
2. Coimbra-Costa D, Alva N, Duran M, et al. Oxidative stress and apoptosis after acute respiratory hypoxia and reoxygenation in rat brain. Redox Biol, 2017, 12: 216-225.
3. Polšek D, Bago M, Živaljić M, et al. A novel adjustable automated system for inducing chronic intermittent hypoxia in mice. Sakakibara M, ed. PLoS ONE, 2017, 12(3): e0174896.
4. Alle H, Roth A, Geiger JRP. Energy-efficient action potentials in hippocampal mossy fibers. Science, 2009, 325(5946): 1405-1408.
5. Harris JJ, Jolivet R, Attwell D. Synaptic energy use and supply. Neuron, 2012, 75(5): 762-777.
6. Cobley JN, Fiorello ML, Bailey DM. 13 reasons why the brain is susceptible to oxidative stress. Redox Biol, 2018, 15: 490-503.
7. Zorov DB, Juhaszova M, Sollott SJ. Mitochondrial ROS-induced ROS release: an update and review. Biochim Biophys Acta, 2006, 1757(5-6): 509-517.
8. Schon EA, Przedborski S. Mitochondria: The Next (Neurode) Generation. Neuron, 2011, 70(6): 1033-1053.
9. 彭万达, 陈锐, 蒋震, 等. 阻塞性睡眠呼吸暂停低通气综合征患者海马及脑白质病变与认知功能的相关性. 中华医学杂志, 2014, 94(10): 724-728.
10. Morrell M. Changes in brain morphology associated with obstructive sleep apnea. Sleep Med, 2003, 4(5): 451-454.
11. Gao H, Han Z, Huang S, et al. Intermittent hypoxia caused cognitive dysfunction relate to miRNAs dysregulation in hippocampus. Behav Brain Res, 2017, 335: 80-87.
12. Jing F, Qi W, Dan Z, et al. Hippocampal impairments are associated with intermittent hypoxia of obstructive sleep apnea. Chin Med J (Engl), 2012, 125(4): 696-701.
13. May A, Mehra R. Obstructive sleep apnea: role of intermittent hypoxia and inflammation. Semin Respir Crit Care Med, 2014, 35(05): 531-544.
14. Wall AM, Corcoran AE, O’Halloran KD, et al. Effects of prolyl-hydroxylase inhibition and chronic intermittent hypoxia on synaptic transmission and plasticity in the rat CA1 and dentate gyrus. Neurobiol Dis, 2014, 62: 8-17.
15. Chou YT, Zhan G, Zhu Y, et al. C/EBP homologous binding protein (CHOP) underlies neural injury in sleep apnea model. Sleep, 2013, 36(4): 481-492.
16. Ugale V, Deshmukh R, Lokwani D, et al. GluN2B subunit selective N-methyl-D-aspartate receptor ligands: democratizing recent progress to assist the development of novel neurotherapeutics. Mol Divers, 2023, 28(3): 1765-1792.
17. Arias-Cavieres A, Khuu MA, Nwakudu CU, et al. A HIF1a-dependent pro-oxidant state disrupts synaptic plasticity and impairs spatial memory in response to intermittent hypoxia. eNeuro, 2020, 7(3): ENEURO.0024-20.2020.
18. Prabhakar NR, Peng YJ, Nanduri J. Hypoxia-inducible factors and obstructive sleep apnea. J Clin Invest, 2020, 130(10): 5042-5051.
19. Mironov SL. Complexity of mitochondrial dynamics in neurons and its control by ADP produced during synaptic activity. Int J Biochem Cell Biol, 2009, 41(10): 2005-2014.
20. Mnatsakanyan N, Jonas EA. The new role of F1Fo ATP synthase in mitochondria-mediated neurodegeneration and neuroprotection. Exp Neurol, 2020, 332: 113400.
21. Douglas RM, Ryu J, Kanaan A, et al. Neuronal death during combined intermittent hypoxia/hypercapnia is due to mitochondrial dysfunction. Am J Physiol Cell Physiol, 2010, 298(6): C1594-C1602.
22. Erecińska M, Silver IA. Tissue oxygen tension and brain sensitivity to hypoxia. Respir Physiol, 2001, 128(3): 263-276.
23. Liochev SI. Reactive oxygen species and the free radical theory of aging. Free Radic Biol Med, 2013, 60: 1-4.
24. Hunter DR, Haworth RA, Southard JH. Relationship between configuration, function, and permeability in calcium-treated mitochondria. J Biol Chem, 1976, 251(16): 5069-5077.
25. Kristián T. Metabolic stages, mitochondria and calcium in hypoxic/ischemic brain damage. Cell Calcium, 2004, 36(3-4): 221-233.
26. Zhou L, Chen P, Peng Y, et al. Role of Oxidative stress in the neurocognitive dysfunction of obstructive sleep apnea syndrome. Oxid Med Cell Longev, 2016, 2016: 1-15.
27. Aoyama K, Watabe M, Nakaki T. Regulation of neuronal glutathione synthesis. J Pharmacol Sci, 2008, 108(3): 227-238.
28. Ling J, Yu Q, Li Y, et al. Edaravone improves intermittent hypoxia-induced cognitive impairment and hippocampal damage in rats. Biol Pharm Bull, 2020, 43(8): 1196-1201.

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