Research progress on mitochondrial mechanism of rehabilitation therapy in the treatment of ischemic stroke_West China Medical Journal

Authors：

LIU Peile ¹ , ZHANG Yixian ¹ , JIANG Xinhong ¹ , CHEN Hongbin ² ,  LIU Nan ¹

1. Department of Rehabilitation, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, P. R. China;
2. Department of Neurology, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, P. R. China;

Corresponding author：

LIU Nan, Email: xieheliunan1984@sina.com

Keywords：

Ischemic stroke; rehabilitation therapy; mitochondria; neural protection; neural plasticity

DOI：

10.7507/1002-0179.202204039

Video：

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Abstract Full text Figures/Tables Video References Cited by

As the “power center” of the cell and the center of metabolic signaling, mitochondria play an important role before, during, and after cerebral ischemia. After ischemic stroke, molecules such as mitoNEET, optic atrophy 1, and mitochondrial division inhibitor 1 can play a neuroprotective role by regulating the state of the mitochondria. Mitochondria are not only energy-supplying organelles, but their biogenesis and movement also play an important role in neuronal growth, differentiation, synapse formation and neural circuit formation after ischemic stroke. Rehabilitation at all stages can play a therapeutic role by modulating mitochondrial function.

Citation： LIU Peile, ZHANG Yixian, JIANG Xinhong, CHEN Hongbin, LIU Nan. Research progress on mitochondrial mechanism of rehabilitation therapy in the treatment of ischemic stroke. West China Medical Journal, 2022, 37(5): 674-679. doi: 10.7507/1002-0179.202204039 Copy

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2.	Baughman JM, Perocchi F, Girgis HS, et al. Integrative genomics identifies MCU as an essential component of the mitochondrial calcium uniporter. Nature, 2011, 476(7360): 341-345.
3.	Ayanga BA, Badal SS, Wang Y, et al. Dynamin-related protein 1 deficiency improves mitochondrial fitness and protects against progression of diabetic nephropathy. J Am Soc Nephrol, 2016, 27(9): 2733-2747.
4.	Rambold AS, Kostelecky B, Elia N, et al. Tubular network formation protects mitochondria from autophagosomal degradation during nutrient starvation. Proc Natl Acad Sci U S A, 2011, 108(25): 10190-10195.
5.	Niizuma K, Yoshioka H, Chen H, et al. Mitochondrial and apoptotic neuronal death signaling pathways in cerebral ischemia. Biochim Biophys Acta, 2010, 1802(1): 92-99.
6.	Endo H, Kamada H, Nito C, et al. Mitochondrial translocation of p53 mediates release of cytochrome C and hippocampal CA1 neuronal death after transient global cerebral ischemia in rats. J Neurosci, 2006, 26(30): 7974-7983.
7.	Andrabi SS, Parvez S, Tabassum H. Ischemic stroke and mitochondria: mechanisms and targets. Protoplasma, 2020, 257(2): 335-343.
8.	Murphy MP. How mitochondria produce reactive oxygen species. Biochem J, 2009, 417(1): 1-13.
9.	Pickles S, Vigié P, Youle RJ. Mitophagy and quality control mechanisms in mitochondrial maintenance. Curr Biol, 2018, 28(4): R170-R185.
10.	Guan R, Zou W, Dai X, et al. Mitophagy, a potential therapeutic target for stroke. J Biomed Sci, 2018, 25(1): 87.
11.	Wu M, Gu X, Ma Z. Mitochondrial quality control in cerebral ischemia-reperfusion injury. Mol Neurobiol, 2021, 58(10): 5253-5271.
12.	He Z, Ning N, Zhou Q, et al. Mitochondria as a therapeutic target for ischemic stroke. Free Radic Biol Med, 2020, 146: 45-58.
13.	Saralkar P, Mdzinarishvili A, Arsiwala TA, et al. The mitochondrial mitoNEET ligand NL-1 is protective in a murine model of transient cerebral ischemic stroke. Pharm Res, 2021, 38(5): 803-817.
14.	Chen H, Vermulst M, Wang Y, et al. Mitochondrial fusion is required for mtDNA stability in skeletal muscle and tolerance of mtDNA mutations. Cell, 2010, 141(2): 280-289.
15.	Lai Y, Lin P, Chen M, et al. Restoration of L-OPA1 alleviates acute ischemic stroke injury in rats via inhibiting neuronal apoptosis and preserving mitochondrial function. Redox Biol, 2020, 34: 101503.
16.	Duan C, Wang L, Zhang J, et al. Mdivi-1 attenuates oxidative stress and exerts vascular protection in ischemic/hypoxic injury by a mechanism independent of Drp1 GTPase activity. Redox Biol, 2020, 37: 101706.
17.	Nhu NT, Li Q, Liu Y, et al. Effects of mdivi-1 on neural mitochondrial dysfunction and mitochondria-mediated apoptosis in ischemia-reperfusion injury after stroke: a systematic review of preclinical studies. Front Mol Neurosci, 2021, 14: 778569.
18.	Wang H, Chen S, Zhang Y, et al. Electroacupuncture ameliorates neuronal injury by Pink1/Parkin-mediated mitophagy clearance in cerebral ischemia-reperfusion. Nitric Oxide, 2019, 91: 23-34.
19.	Zhang X, Yan H, Yuan Y, et al. Cerebral ischemia-reperfusion-induced autophagy protects against neuronal injury by mitochondrial clearance. Autophagy, 2013, 9(9): 1321-1333.
20.	Wen H, Li L, Zhan L, et al. Hypoxic postconditioning promotes mitophagy against transient global cerebral ischemia via PINK1/Parkin-induced mitochondrial ubiquitination in adult rats. Cell Death Dis, 2021, 12(7): 630.
21.	Bai F, Guo F, Jiang T, et al. Arachidonyl-2-chloroethylamide alleviates cerebral ischemia injury through glycogen synthase kinase-3β-mediated mitochondrial biogenesis and functional improvement. Mol Neurobiol, 2017, 54(2): 1240-1253.
22.	Kang JS, Tian JH, Pan PY, et al. Docking of axonal mitochondria by syntaphilin controls their mobility and affects short-term facilitation. Cell, 2008, 132(1): 137-148.
23.	Gutsaeva DR, Carraway MS, Suliman HB, et al. Transient hypoxia stimulates mitochondrial biogenesis in brain subcortex by a neuronal nitric oxide synthase-dependent mechanism. J Neurosci, 2008, 28(9): 2015-2024.
24.	Renton JP, Xu N, Clark JJ, et al. Interaction of neurotrophin signaling with Bcl-2 localized to the mitochondria and endoplasmic reticulum on spiral ganglion neuron survival and neurite growth. J Neurosci Res, 2010, 88(10): 2239-2251.
25.	Hebert TL, Wu X, Yu G, et al. Culture effects of epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) on cryopreserved human adipose-derived stromal/stem cell proliferation and adipogenesis. J Tissue Eng Regen Med, 2009, 3(7): 553-561.
26.	Raefsky SM, Mattson MP. Adaptive responses of neuronal mitochondria to bioenergetic challenges: roles in neuroplasticity and disease resistance. Free Radic Biol Med, 2017, 102: 203-216.
27.	Mattson MP, Partin J. Evidence for mitochondrial control of neuronal polarity. J Neurosci Res, 1999, 56(1): 8-20.
28.	Cheng A, Wan R, Yang JL, et al. Involvement of PGC-1α in the formation and maintenance of neuronal dendritic spines. Nat Commun, 2012, 3: 1250.
29.	Habash T, Saleh A, Roy Chowdhury SK, et al. The proinflammatory cytokine, interleukin-17A, augments mitochondrial function and neurite outgrowth of cultured adult sensory neurons derived from normal and diabetic rats. Exp Neurol, 2015, 273: 177-189.
30.	Hafez S, Eid Z, Alabasi S, et al. Mechanisms of preconditioning exercise-induced neurovascular protection in stroke. J Stroke, 2021, 23(3): 312-326.
31.	李宏玉, 唐强, 朱路文, 等. 运动预处理对脑缺血再灌注大鼠线粒体 ATP 敏感性钾通道蛋白及细胞凋亡的影响. 中国康复理论与实践, 2018, 24(5): 497-501.
32.	Zhang L, He Z, Zhang Q, et al. Exercise pretreatment promotes mitochondrial dynamic protein OPA1 expression after cerebral ischemia in rats. Int J Mol Sci, 2014, 15(3): 4453-4463.
33.	Hentia C, Rizzato A, Camporesi E, et al. An overview of protective strategies against ischemia/reperfusion injury: the role of hyperbaric oxygen preconditioning. Brain Behav, 2018, 8(5): e00959.
34.	Wang SD, Fu YY, Han XY, et al. Hyperbaric oxygen preconditioning protects against cerebral ischemia/reperfusion injury by inhibiting mitochondrial apoptosis and energy metabolism disturbance. Neurochem Res, 2021, 46(4): 866-877.
35.	McDonald MW, Dykes A, Jeffers MS, et al. Remote ischemic conditioning and stroke recovery. Neurorehabil Neural Repair, 2021, 35(6): 545-549.
36.	Briones TL, Suh E, Jozsa L, et al. Changes in number of synapses and mitochondria in presynaptic terminals in the dentate gyrus following cerebral ischemia and rehabilitation training. Brain Res, 2005, 1033(1): 51-57.
37.	Nhu NT, Cheng YJ, Lee SD. Effects of treadmill exercise on neural mitochondrial functions in Parkinson’s disease: a systematic review of animal studies. Biomedicines, 2021, 9(8): 1011.
38.	Zhang Q, Wu Y, Sha HY, et al. Early exercise affects mitochondrial transcription factors expression after cerebral ischemia in rats. Int J Mol Sci, 2012, 13(2): 1670-1679.
39.	Gendi F, Pei F, Wang Y, et al. Mitochondrial proteins unveil the mechanism by which physical exercise ameliorates memory, learning and motor activity in hypoxic ischemic encephalopathy rat model. Int J Mol Sci, 2022, 23(8): 4235.
40.	Li C, Zhang B, Tian S, et al. Early wheel-running promotes functional recovery by improving mitochondria metabolism in olfactory ensheathing cells after ischemic stroke in rats. Behav Brain Res, 2019, 361: 32-38.
41.	Liu Y, Zhu C, Guo J, et al. The neuroprotective effect of irisin in ischemic stroke. Front Aging Neurosci, 2020, 12: 588958.
42.	Pan G, Zhang H, Zhu A, et al. Treadmill exercise attenuates cerebral ischaemic injury in rats by protecting mitochondrial function via enhancement of caveolin-1. Life Sci, 2021, 264: 118634.
43.	Martínez-Guardado I, Arboleya S, Grijota FJ, et al. The therapeutic role of exercise and probiotics in stressful brain conditions. Int J Mol Sci, 2022, 23(7): 3610.
44.	Chen B, Lin WQ, Li ZF, et al. Electroacupuncture attenuates ischemic brain injury and cellular apoptosis via mitochondrial translocation of cofilin. Chin J Integr Med, 2021, 27(9): 705-712.
45.	Tian WQ, Peng YG, Cui SY, et al. Effects of electroacupuncture of different intensities on energy metabolism of mitochondria of brain cells in rats with cerebral ischemia-reperfusion injury. Chin J Integr Med, 2015, 21(8): 618-623.
46.	Yu K, Kuang S, Wang C, et al. Changes in mitochondria-associated protein expression and mitochondrial function in response to 2 weeks of enriched environment training after cerebral ischaemia-reperfusion injury. J Mol Neurosci, 2020, 70(3): 413-421.
47.	Bennett MH, Wasiak J, Schnabel A, et al. Hyperbaric oxygen therapy for acute ischaemic stroke. Cochrane Database Syst Rev, 2014(11): CD004954.
48.	Cozene B, Sadanandan N, Gonzales-Portillo B, et al. An extra breath of fresh air: hyperbaric oxygenation as a stroke therapeutic. Biomolecules, 2020, 10(9): 1279.
49.	Rosario ER, Kaplan SE, Khonsari S, et al. The effect of hyperbaric oxygen therapy on functional impairments caused by ischemic stroke. Neurol Res Int, 2018, 2018: 3172679.
50.	Hadanny A, Rittblat M, Bitterman M, et al. Hyperbaric oxygen therapy improves neurocognitive functions of post-stroke patients: a retrospective analysis. Restor Neurol Neurosci, 2020, 38(1): 93-107.
51.	于秋红, 刘亚玲, 王丛, 等. 高压氧对大脑中动脉阻塞大鼠细胞凋亡的影响. 中华物理医学与康复杂志, 2019, 41(8): 561-564.
52.	于秋红, 李婕, 刘亚玲, 等. 高压氧治疗对局灶性脑梗死大鼠的神经保护作用. 中国卒中杂志, 2020, 15(8): 830-835.

1. Nunnari J, Suomalainen A. Mitochondria: in sickness and in health. Cell, 2012, 148(6): 1145-1159.
2. Baughman JM, Perocchi F, Girgis HS, et al. Integrative genomics identifies MCU as an essential component of the mitochondrial calcium uniporter. Nature, 2011, 476(7360): 341-345.
3. Ayanga BA, Badal SS, Wang Y, et al. Dynamin-related protein 1 deficiency improves mitochondrial fitness and protects against progression of diabetic nephropathy. J Am Soc Nephrol, 2016, 27(9): 2733-2747.
4. Rambold AS, Kostelecky B, Elia N, et al. Tubular network formation protects mitochondria from autophagosomal degradation during nutrient starvation. Proc Natl Acad Sci U S A, 2011, 108(25): 10190-10195.
5. Niizuma K, Yoshioka H, Chen H, et al. Mitochondrial and apoptotic neuronal death signaling pathways in cerebral ischemia. Biochim Biophys Acta, 2010, 1802(1): 92-99.
6. Endo H, Kamada H, Nito C, et al. Mitochondrial translocation of p53 mediates release of cytochrome C and hippocampal CA1 neuronal death after transient global cerebral ischemia in rats. J Neurosci, 2006, 26(30): 7974-7983.
7. Andrabi SS, Parvez S, Tabassum H. Ischemic stroke and mitochondria: mechanisms and targets. Protoplasma, 2020, 257(2): 335-343.
8. Murphy MP. How mitochondria produce reactive oxygen species. Biochem J, 2009, 417(1): 1-13.
9. Pickles S, Vigié P, Youle RJ. Mitophagy and quality control mechanisms in mitochondrial maintenance. Curr Biol, 2018, 28(4): R170-R185.
10. Guan R, Zou W, Dai X, et al. Mitophagy, a potential therapeutic target for stroke. J Biomed Sci, 2018, 25(1): 87.
11. Wu M, Gu X, Ma Z. Mitochondrial quality control in cerebral ischemia-reperfusion injury. Mol Neurobiol, 2021, 58(10): 5253-5271.
12. He Z, Ning N, Zhou Q, et al. Mitochondria as a therapeutic target for ischemic stroke. Free Radic Biol Med, 2020, 146: 45-58.
13. Saralkar P, Mdzinarishvili A, Arsiwala TA, et al. The mitochondrial mitoNEET ligand NL-1 is protective in a murine model of transient cerebral ischemic stroke. Pharm Res, 2021, 38(5): 803-817.
14. Chen H, Vermulst M, Wang Y, et al. Mitochondrial fusion is required for mtDNA stability in skeletal muscle and tolerance of mtDNA mutations. Cell, 2010, 141(2): 280-289.
15. Lai Y, Lin P, Chen M, et al. Restoration of L-OPA1 alleviates acute ischemic stroke injury in rats via inhibiting neuronal apoptosis and preserving mitochondrial function. Redox Biol, 2020, 34: 101503.
16. Duan C, Wang L, Zhang J, et al. Mdivi-1 attenuates oxidative stress and exerts vascular protection in ischemic/hypoxic injury by a mechanism independent of Drp1 GTPase activity. Redox Biol, 2020, 37: 101706.
17. Nhu NT, Li Q, Liu Y, et al. Effects of mdivi-1 on neural mitochondrial dysfunction and mitochondria-mediated apoptosis in ischemia-reperfusion injury after stroke: a systematic review of preclinical studies. Front Mol Neurosci, 2021, 14: 778569.
18. Wang H, Chen S, Zhang Y, et al. Electroacupuncture ameliorates neuronal injury by Pink1/Parkin-mediated mitophagy clearance in cerebral ischemia-reperfusion. Nitric Oxide, 2019, 91: 23-34.
19. Zhang X, Yan H, Yuan Y, et al. Cerebral ischemia-reperfusion-induced autophagy protects against neuronal injury by mitochondrial clearance. Autophagy, 2013, 9(9): 1321-1333.
20. Wen H, Li L, Zhan L, et al. Hypoxic postconditioning promotes mitophagy against transient global cerebral ischemia via PINK1/Parkin-induced mitochondrial ubiquitination in adult rats. Cell Death Dis, 2021, 12(7): 630.
21. Bai F, Guo F, Jiang T, et al. Arachidonyl-2-chloroethylamide alleviates cerebral ischemia injury through glycogen synthase kinase-3β-mediated mitochondrial biogenesis and functional improvement. Mol Neurobiol, 2017, 54(2): 1240-1253.
22. Kang JS, Tian JH, Pan PY, et al. Docking of axonal mitochondria by syntaphilin controls their mobility and affects short-term facilitation. Cell, 2008, 132(1): 137-148.
23. Gutsaeva DR, Carraway MS, Suliman HB, et al. Transient hypoxia stimulates mitochondrial biogenesis in brain subcortex by a neuronal nitric oxide synthase-dependent mechanism. J Neurosci, 2008, 28(9): 2015-2024.
24. Renton JP, Xu N, Clark JJ, et al. Interaction of neurotrophin signaling with Bcl-2 localized to the mitochondria and endoplasmic reticulum on spiral ganglion neuron survival and neurite growth. J Neurosci Res, 2010, 88(10): 2239-2251.
25. Hebert TL, Wu X, Yu G, et al. Culture effects of epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) on cryopreserved human adipose-derived stromal/stem cell proliferation and adipogenesis. J Tissue Eng Regen Med, 2009, 3(7): 553-561.
26. Raefsky SM, Mattson MP. Adaptive responses of neuronal mitochondria to bioenergetic challenges: roles in neuroplasticity and disease resistance. Free Radic Biol Med, 2017, 102: 203-216.
27. Mattson MP, Partin J. Evidence for mitochondrial control of neuronal polarity. J Neurosci Res, 1999, 56(1): 8-20.
28. Cheng A, Wan R, Yang JL, et al. Involvement of PGC-1α in the formation and maintenance of neuronal dendritic spines. Nat Commun, 2012, 3: 1250.
29. Habash T, Saleh A, Roy Chowdhury SK, et al. The proinflammatory cytokine, interleukin-17A, augments mitochondrial function and neurite outgrowth of cultured adult sensory neurons derived from normal and diabetic rats. Exp Neurol, 2015, 273: 177-189.
30. Hafez S, Eid Z, Alabasi S, et al. Mechanisms of preconditioning exercise-induced neurovascular protection in stroke. J Stroke, 2021, 23(3): 312-326.
31. 李宏玉, 唐强, 朱路文, 等. 运动预处理对脑缺血再灌注大鼠线粒体 ATP 敏感性钾通道蛋白及细胞凋亡的影响. 中国康复理论与实践, 2018, 24(5): 497-501.
32. Zhang L, He Z, Zhang Q, et al. Exercise pretreatment promotes mitochondrial dynamic protein OPA1 expression after cerebral ischemia in rats. Int J Mol Sci, 2014, 15(3): 4453-4463.
33. Hentia C, Rizzato A, Camporesi E, et al. An overview of protective strategies against ischemia/reperfusion injury: the role of hyperbaric oxygen preconditioning. Brain Behav, 2018, 8(5): e00959.
34. Wang SD, Fu YY, Han XY, et al. Hyperbaric oxygen preconditioning protects against cerebral ischemia/reperfusion injury by inhibiting mitochondrial apoptosis and energy metabolism disturbance. Neurochem Res, 2021, 46(4): 866-877.
35. McDonald MW, Dykes A, Jeffers MS, et al. Remote ischemic conditioning and stroke recovery. Neurorehabil Neural Repair, 2021, 35(6): 545-549.
36. Briones TL, Suh E, Jozsa L, et al. Changes in number of synapses and mitochondria in presynaptic terminals in the dentate gyrus following cerebral ischemia and rehabilitation training. Brain Res, 2005, 1033(1): 51-57.
37. Nhu NT, Cheng YJ, Lee SD. Effects of treadmill exercise on neural mitochondrial functions in Parkinson’s disease: a systematic review of animal studies. Biomedicines, 2021, 9(8): 1011.
38. Zhang Q, Wu Y, Sha HY, et al. Early exercise affects mitochondrial transcription factors expression after cerebral ischemia in rats. Int J Mol Sci, 2012, 13(2): 1670-1679.
39. Gendi F, Pei F, Wang Y, et al. Mitochondrial proteins unveil the mechanism by which physical exercise ameliorates memory, learning and motor activity in hypoxic ischemic encephalopathy rat model. Int J Mol Sci, 2022, 23(8): 4235.
40. Li C, Zhang B, Tian S, et al. Early wheel-running promotes functional recovery by improving mitochondria metabolism in olfactory ensheathing cells after ischemic stroke in rats. Behav Brain Res, 2019, 361: 32-38.
41. Liu Y, Zhu C, Guo J, et al. The neuroprotective effect of irisin in ischemic stroke. Front Aging Neurosci, 2020, 12: 588958.
42. Pan G, Zhang H, Zhu A, et al. Treadmill exercise attenuates cerebral ischaemic injury in rats by protecting mitochondrial function via enhancement of caveolin-1. Life Sci, 2021, 264: 118634.
43. Martínez-Guardado I, Arboleya S, Grijota FJ, et al. The therapeutic role of exercise and probiotics in stressful brain conditions. Int J Mol Sci, 2022, 23(7): 3610.
44. Chen B, Lin WQ, Li ZF, et al. Electroacupuncture attenuates ischemic brain injury and cellular apoptosis via mitochondrial translocation of cofilin. Chin J Integr Med, 2021, 27(9): 705-712.
45. Tian WQ, Peng YG, Cui SY, et al. Effects of electroacupuncture of different intensities on energy metabolism of mitochondria of brain cells in rats with cerebral ischemia-reperfusion injury. Chin J Integr Med, 2015, 21(8): 618-623.
46. Yu K, Kuang S, Wang C, et al. Changes in mitochondria-associated protein expression and mitochondrial function in response to 2 weeks of enriched environment training after cerebral ischaemia-reperfusion injury. J Mol Neurosci, 2020, 70(3): 413-421.
47. Bennett MH, Wasiak J, Schnabel A, et al. Hyperbaric oxygen therapy for acute ischaemic stroke. Cochrane Database Syst Rev, 2014(11): CD004954.
48. Cozene B, Sadanandan N, Gonzales-Portillo B, et al. An extra breath of fresh air: hyperbaric oxygenation as a stroke therapeutic. Biomolecules, 2020, 10(9): 1279.
49. Rosario ER, Kaplan SE, Khonsari S, et al. The effect of hyperbaric oxygen therapy on functional impairments caused by ischemic stroke. Neurol Res Int, 2018, 2018: 3172679.
50. Hadanny A, Rittblat M, Bitterman M, et al. Hyperbaric oxygen therapy improves neurocognitive functions of post-stroke patients: a retrospective analysis. Restor Neurol Neurosci, 2020, 38(1): 93-107.
51. 于秋红, 刘亚玲, 王丛, 等. 高压氧对大脑中动脉阻塞大鼠细胞凋亡的影响. 中华物理医学与康复杂志, 2019, 41(8): 561-564.
52. 于秋红, 李婕, 刘亚玲, 等. 高压氧治疗对局灶性脑梗死大鼠的神经保护作用. 中国卒中杂志, 2020, 15(8): 830-835.

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