Advances of the role of mitochondrial dysfunction in the spinal cord injury and its relevant treatments_Chinese Journal of Reparative and Reconstructive Surgery

Authors：

MIAO Xin , LIN Junqing ,  ZHENG Xianyou

Department of Orthopedic Surgery, Shanghai Sixth People’s Hospital, Shanghai Jiao Tong University, Shanghai, 200233, P. R. China;

Corresponding author：

ZHENG Xianyou, Email: zhengxianyou@126.com

Keywords：

Spinal cord injury; mitochondrial dysfunction; therapeutic strategies

DOI：

10.7507/1002-1892.202203081

Video：

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Objective To review the advances of the role of mitochondrial dysfunction in the spinal cord injury (SCI) and its relevant treatments. Methods Focusing on various mechanisms of mitochondrial dysfunction, recent relevant literature at home and abroad was identified to summarize the therapeutic strategies for SCI. Results Mitochondrial dysfunction is mainly manifested in abnormalities in mitochondrial energy metabolism, mitochondrial oxidative stress, mitochondrial-mediated apoptosis, mitophagy, mitochondrial permeability transition, and mitochondrial biogenesis, playing a vital role in the development of SCI. Drug that enhanced mitochondrial function have been proved beneficial for the treatment of SCI. Conclusion Mitochondrial dysfunction can serve as a potential therapeutic target for SCI, providing ideas and basis for the development of SCI therapeutic candidates in the future.

Citation： MIAO Xin, LIN Junqing, ZHENG Xianyou. Advances of the role of mitochondrial dysfunction in the spinal cord injury and its relevant treatments. Chinese Journal of Reparative and Reconstructive Surgery, 2022, 36(7): 902-907. doi: 10.7507/1002-1892.202203081 Copy

1.	Fischer I, Dulin JN, Lane MA. Transplanting neural progenitor cells to restore connectivity after spinal cord injury. Nat Rev Neurosci, 2020, 21(7): 366-383.
2.	Bie F, Wang K, Xu T, et al. The potential roles of circular RNAs as modulators in traumatic spinal cord injury. Biomed Pharmacother, 2021, 141: 111826. doi: 10.1016/j.biopha.2021.111826.
3.	Lin J, Xiong Z, Gu J, et al. Sirtuins: Potential therapeutic targets for defense against oxidative stress in spinal cord injury. Oxid Med Cell Longev, 2021, 2021: 7207692. doi: 10.1155/2021/7207692.
4.	Flack JA, Sharma KD, Xie JY. Delving into the recent advancements of spinal cord injury treatment: a review of recent progress. Neural Regen Res, 2022, 17(2): 283-291.
5.	Quadri SA, Farooqui M, Ikram A, et al. Recent update on basic mechanisms of spinal cord injury. Neurosurg Rev, 2020, 43(2): 425-441.
6.	Jiang M, Bai M, Lei J, et al. Mitochondrial dysfunction and the AKI-to-CKD transition. Am J Physiol Renal Physiol, 2020, 319(6): F1105-F1116.
7.	Andrabi SS, Yang J, Gao Y, et al. Nanoparticles with antioxidant enzymes protect injured spinal cord from neuronal cell apoptosis by attenuating mitochondrial dysfunction. J Control Release, 2020, 317: 300-311.
8.	Slater PG, Domínguez-Romero ME, Villarreal M, et al. Mitochondrial function in spinal cord injury and regeneration. Cell Mol Life Sci, 2022, 79(5): 239. doi: 10.1007/s00018-022-04261-x.
9.	Fan B, Wei Z, Feng S. Progression in translational research on spinal cord injury based on microenvironment imbalance. Bone Res, 2022, 10(1): 35. doi: 10.1038/s41413-022-00199-9.
10.	Hou Y, Luan J, Huang T, et al. Tauroursodeoxycholic acid alleviates secondary injury in spinal cord injury mice by reducing oxidative stress, apoptosis, and inflammatory response. J Neuroinflammation, 2021, 18(1): 216. doi: 10.1186/s12974-021-02248-2.
11.	Anjum A, Yazid MD, Fauzi Daud M, et al. Spinal cord injury: Pathophysiology, multimolecular interactions, and underlying recovery mechanisms. Int J Mol Sci, 2020, 21(20): 7533. doi: 10.3390/ijms21207533.
12.	McEwen ML, Sullivan PG, Rabchevsky AG, et al. Targeting mitochondrial function for the treatment of acute spinal cord injury. Neurotherapeutics, 2011, 8(2): 168-179.
13.	Springer JE, Prajapati P, Sullivan PG. Targeting the mitochondrial permeability transition pore in traumatic central nervous system injury. Neural Regen Res, 2018, 13(8): 1338-1341.
14.	Baroncini A, Maffulli N, Eschweiler J, et al. Pharmacological management of secondary spinal cord injury. Expert Opin Pharmacother, 2021, 22(13): 1793-1800.
15.	Scholpa NE, Schnellmann RG. Mitochondrial-based therapeutics for the treatment of spinal cord injury: Mitochondrial biogenesis as a potential pharmacological target. J Pharmacol Exp Ther, 2017, 363(3): 303-313.
16.	Patel SP, Sullivan PG, Lyttle TS, et al. Acetyl-L-carnitine treatment following spinal cord injury improves mitochondrial function correlated with remarkable tissue sparing and functional recovery. Neuroscience, 2012, 210: 296-307.
17.	Patel SP, Sullivan PG, Pandya JD, et al. N-acetylcysteine amide preserves mitochondrial bioenergetics and improves functional recovery following spinal trauma. Exp Neurol, 2014, 257: 95-105.
18.	Wang H, Zheng Z, Han W, et al. Metformin promotes axon regeneration after spinal cord injury through inhibiting oxidative stress and stabilizing microtubule. Oxid Med Cell Longev, 2020, 2020: 9741369. doi: 10.1155/2020/9741369.
19.	Kim JW, Mahapatra C, Hong JY, et al. Functional recovery of contused spinal cord in rat with the injection of optimal-dosed cerium oxide nanoparticles. Adv Sci (Weinh), 2017, 4(10): 1700034. doi: 10.1002/advs.201700034.
20.	Luo W, Wang Y, Lin F, et al. Selenium-doped carbon quantum dots efficiently ameliorate secondary spinal cord injury via scavenging reactive oxygen species. Int J Nanomedicine, 2020, 15: 10113-10125.
21.	Wang Y, Jiao J, Zhang S, et al. RIP3 inhibition protects locomotion function through ameliorating mitochondrial antioxidative capacity after spinal cord injury. Biomed Pharmacother, 2019, 116: 109019. doi: 10.1016/j.biopha.2019.109019.
22.	Shi Z, Yuan S, Shi L, et al. Programmed cell death in spinal cord injury pathogenesis and therapy. Cell Prolif, 2021, 54(3): e12992. doi: doi: 10.1111/cpr.12992.
23.	Ying Y, Zhang Y, Tu Y, et al. Hypoxia response element-directed expression of aFGF in neural stem cells promotes the recovery of spinal cord injury and attenuates SCI-induced apoptosis. Front Cell Dev Biol, 2021, 9: 693694. doi: 10.3389/fcell.2021.693694.
24.	Bock FJ, Tait SWG. Mitochondria as multifaceted regulators of cell death. Nat Rev Mol Cell Biol, 2020, 21(2): 85-100.
25.	Rabchevsky AG, Michael FM, Patel SP. Mitochondria focused neurotherapeutics for spinal cord injury. Exp Neurol, 2020, 330: 113332. doi: doi: 10.1016/j.expneurol.2020.113332.
26.	Abbaszadeh F, Fakhri S, Khan H. Targeting apoptosis and autophagy following spinal cord injury: Therapeutic approaches to polyphenols and candidate phytochemicals. Pharmacol Res, 2020, 160: 105069. doi: 10.1016/j.phrs.2020.105069.
27.	Zhang Q, Xiong Y, Li B, et al. Total flavonoids of hawthorn leaves promote motor function recovery via inhibition of apoptosis after spinal cord injury. Neural Regen Res, 2021, 16(2): 350-356.
28.	Zhao R, Wu X, Bi XY, et al. Baicalin attenuates blood-spinal cord barrier disruption and apoptosis through PI3K/Akt signaling pathway after spinal cord injury. Neural Regen Res, 2022, 17(5): 1080-1087.
29.	Zhu M, Huang X, Shan H, et al. Mitophagy in traumatic brain injury: A New target for therapeutic intervention. Oxid Med Cell Longev, 2022, 2022: 4906434. doi: 10.1155/2022/4906434.
30.	Mao Y, Du J, Chen X, et al. Maltol promotes mitophagy and inhibits oxidative stress via the nrf2/pink1/parkin pathway after spinal cord injury. Oxid Med Cell Longev, 2022, 2022: 1337630. doi: 10.1155/2022/1337630.
31.	Kim SY, Shim MS, Kim KY, et al. Inhibition of cyclophilin D by cyclosporin A promotes retinal ganglion cell survival by preventing mitochondrial alteration in ischemic injury. Cell Death Dis, 2014, 5(3): e1105. doi: 10.1038/cddis.2014.80.
32.	Liu K, Yan L, Jiang X, et al. Acquired inhibition of microRNA-124 protects against spinal cord ischemia-reperfusion injury partially through a mitophagy-dependent pathway. J Thorac Cardiovasc Surg, 2017, 154(5): 1498-1508.
33.	Li Q, Gao S, Kang Z, et al. Rapamycin enhances mitophagy and attenuates apoptosis after spinal ischemia-reperfusion injury. Front Neurosci, 2018, 12: 865. doi: 10.3389/fnins.2018.00865.
34.	Neginskaya MA, Pavlov EV, Sheu SS. Electrophysiological properties of the mitochondrial permeability transition pores: Channel diversity and disease implication. Biochim Biophys Acta Bioenerg, 2021, 1862(3): 148357. doi: 10.1016/j.bbabio.2020.148357.
35.	Wang S, Smith GM, Selzer ME, et al. Emerging molecular therapeutic targets for spinal cord injury. Expert Opin Ther Targets, 2019, 23(9): 787-803.
36.	Springer JE, Visavadiya NP, Sullivan PG, et al. Post-injury treatment with NIM811 promotes recovery of function in adult female rats after spinal cord contusion: A dose-response study. J Neurotrauma, 2018, 35(3): 492-499.
37.	Simmons EC, Scholpa NE, Schnellmann RG. FDA-approved 5-HT_1F receptor agonist lasmiditan induces mitochondrial biogenesis and enhances locomotor and blood-spinal cord barrier recovery after spinal cord injury. Exp Neurol, 2021, 341: 113720. doi: 10.1016/j.expneurol.2021.113720.
38.	Simmons EC, Scholpa NE, Schnellmann RG. Mitochondrial biogenesis as a therapeutic target for traumatic and neurodegenerative CNS diseases. Exp Neurol, 2020, 329: 113309. doi: 10.1016/j.expneurol.2020.113309.
39.	Cardanho-Ramos C, Morais VA. Mitochondrial biogenesis in neurons: How and where. Int J Mol Sci, 2021, 22(23): 13059. doi: 10.3390/ijms222313059.
40.	Hu J, Lang Y, Zhang T, et al. Lentivirus-mediated PGC-1α overexpression protects against traumatic spinal cord injury in rats. Neuroscience, 2016, 328: 40-49.
41.	Hu J, Lang Y, Cao Y, et al. The neuroprotective effect of tetramethylpyrazine against contusive spinal cord injury by activating PGC-1α in rats. Neurochem Res, 2015, 40(7): 1393-1401.
42.	Scholpa NE, Williams H, Wang W, et al. Pharmacological stimulation of mitochondrial biogenesis using the food and drug administration-approved beta2-adrenoreceptor agonist formoterol for the treatment of spinal cord injury. J Neurotrauma, 2019, 36(6): 962-972.
43.	Scholpa NE, Simmons EC, Crossman JD, et al. Time-to-treatment window and cross-sex potential of β₂-adrenergic receptor-induced mitochondrial biogenesis-mediated recovery after spinal cord injury. Toxicol Appl Pharmacol, 2021, 411: 115366. doi: 10.1016/j.taap.2020.115366.
44.	Simmons EC, Scholpa NE, Cleveland KH, et al. 5-hydroxytryptamine 1F receptor agonist induces mitochondrial biogenesis and promotes recovery from spinal cord injury. J Pharmacol Exp Ther, 2020, 372(2): 216-223.

1. Fischer I, Dulin JN, Lane MA. Transplanting neural progenitor cells to restore connectivity after spinal cord injury. Nat Rev Neurosci, 2020, 21(7): 366-383.
2. Bie F, Wang K, Xu T, et al. The potential roles of circular RNAs as modulators in traumatic spinal cord injury. Biomed Pharmacother, 2021, 141: 111826. doi: 10.1016/j.biopha.2021.111826.
3. Lin J, Xiong Z, Gu J, et al. Sirtuins: Potential therapeutic targets for defense against oxidative stress in spinal cord injury. Oxid Med Cell Longev, 2021, 2021: 7207692. doi: 10.1155/2021/7207692.
4. Flack JA, Sharma KD, Xie JY. Delving into the recent advancements of spinal cord injury treatment: a review of recent progress. Neural Regen Res, 2022, 17(2): 283-291.
5. Quadri SA, Farooqui M, Ikram A, et al. Recent update on basic mechanisms of spinal cord injury. Neurosurg Rev, 2020, 43(2): 425-441.
6. Jiang M, Bai M, Lei J, et al. Mitochondrial dysfunction and the AKI-to-CKD transition. Am J Physiol Renal Physiol, 2020, 319(6): F1105-F1116.
7. Andrabi SS, Yang J, Gao Y, et al. Nanoparticles with antioxidant enzymes protect injured spinal cord from neuronal cell apoptosis by attenuating mitochondrial dysfunction. J Control Release, 2020, 317: 300-311.
8. Slater PG, Domínguez-Romero ME, Villarreal M, et al. Mitochondrial function in spinal cord injury and regeneration. Cell Mol Life Sci, 2022, 79(5): 239. doi: 10.1007/s00018-022-04261-x.
9. Fan B, Wei Z, Feng S. Progression in translational research on spinal cord injury based on microenvironment imbalance. Bone Res, 2022, 10(1): 35. doi: 10.1038/s41413-022-00199-9.
10. Hou Y, Luan J, Huang T, et al. Tauroursodeoxycholic acid alleviates secondary injury in spinal cord injury mice by reducing oxidative stress, apoptosis, and inflammatory response. J Neuroinflammation, 2021, 18(1): 216. doi: 10.1186/s12974-021-02248-2.
11. Anjum A, Yazid MD, Fauzi Daud M, et al. Spinal cord injury: Pathophysiology, multimolecular interactions, and underlying recovery mechanisms. Int J Mol Sci, 2020, 21(20): 7533. doi: 10.3390/ijms21207533.
12. McEwen ML, Sullivan PG, Rabchevsky AG, et al. Targeting mitochondrial function for the treatment of acute spinal cord injury. Neurotherapeutics, 2011, 8(2): 168-179.
13. Springer JE, Prajapati P, Sullivan PG. Targeting the mitochondrial permeability transition pore in traumatic central nervous system injury. Neural Regen Res, 2018, 13(8): 1338-1341.
14. Baroncini A, Maffulli N, Eschweiler J, et al. Pharmacological management of secondary spinal cord injury. Expert Opin Pharmacother, 2021, 22(13): 1793-1800.
15. Scholpa NE, Schnellmann RG. Mitochondrial-based therapeutics for the treatment of spinal cord injury: Mitochondrial biogenesis as a potential pharmacological target. J Pharmacol Exp Ther, 2017, 363(3): 303-313.
16. Patel SP, Sullivan PG, Lyttle TS, et al. Acetyl-L-carnitine treatment following spinal cord injury improves mitochondrial function correlated with remarkable tissue sparing and functional recovery. Neuroscience, 2012, 210: 296-307.
17. Patel SP, Sullivan PG, Pandya JD, et al. N-acetylcysteine amide preserves mitochondrial bioenergetics and improves functional recovery following spinal trauma. Exp Neurol, 2014, 257: 95-105.
18. Wang H, Zheng Z, Han W, et al. Metformin promotes axon regeneration after spinal cord injury through inhibiting oxidative stress and stabilizing microtubule. Oxid Med Cell Longev, 2020, 2020: 9741369. doi: 10.1155/2020/9741369.
19. Kim JW, Mahapatra C, Hong JY, et al. Functional recovery of contused spinal cord in rat with the injection of optimal-dosed cerium oxide nanoparticles. Adv Sci (Weinh), 2017, 4(10): 1700034. doi: 10.1002/advs.201700034.
20. Luo W, Wang Y, Lin F, et al. Selenium-doped carbon quantum dots efficiently ameliorate secondary spinal cord injury via scavenging reactive oxygen species. Int J Nanomedicine, 2020, 15: 10113-10125.
21. Wang Y, Jiao J, Zhang S, et al. RIP3 inhibition protects locomotion function through ameliorating mitochondrial antioxidative capacity after spinal cord injury. Biomed Pharmacother, 2019, 116: 109019. doi: 10.1016/j.biopha.2019.109019.
22. Shi Z, Yuan S, Shi L, et al. Programmed cell death in spinal cord injury pathogenesis and therapy. Cell Prolif, 2021, 54(3): e12992. doi: doi: 10.1111/cpr.12992.
23. Ying Y, Zhang Y, Tu Y, et al. Hypoxia response element-directed expression of aFGF in neural stem cells promotes the recovery of spinal cord injury and attenuates SCI-induced apoptosis. Front Cell Dev Biol, 2021, 9: 693694. doi: 10.3389/fcell.2021.693694.
24. Bock FJ, Tait SWG. Mitochondria as multifaceted regulators of cell death. Nat Rev Mol Cell Biol, 2020, 21(2): 85-100.
25. Rabchevsky AG, Michael FM, Patel SP. Mitochondria focused neurotherapeutics for spinal cord injury. Exp Neurol, 2020, 330: 113332. doi: doi: 10.1016/j.expneurol.2020.113332.
26. Abbaszadeh F, Fakhri S, Khan H. Targeting apoptosis and autophagy following spinal cord injury: Therapeutic approaches to polyphenols and candidate phytochemicals. Pharmacol Res, 2020, 160: 105069. doi: 10.1016/j.phrs.2020.105069.
27. Zhang Q, Xiong Y, Li B, et al. Total flavonoids of hawthorn leaves promote motor function recovery via inhibition of apoptosis after spinal cord injury. Neural Regen Res, 2021, 16(2): 350-356.
28. Zhao R, Wu X, Bi XY, et al. Baicalin attenuates blood-spinal cord barrier disruption and apoptosis through PI3K/Akt signaling pathway after spinal cord injury. Neural Regen Res, 2022, 17(5): 1080-1087.
29. Zhu M, Huang X, Shan H, et al. Mitophagy in traumatic brain injury: A New target for therapeutic intervention. Oxid Med Cell Longev, 2022, 2022: 4906434. doi: 10.1155/2022/4906434.
30. Mao Y, Du J, Chen X, et al. Maltol promotes mitophagy and inhibits oxidative stress via the nrf2/pink1/parkin pathway after spinal cord injury. Oxid Med Cell Longev, 2022, 2022: 1337630. doi: 10.1155/2022/1337630.
31. Kim SY, Shim MS, Kim KY, et al. Inhibition of cyclophilin D by cyclosporin A promotes retinal ganglion cell survival by preventing mitochondrial alteration in ischemic injury. Cell Death Dis, 2014, 5(3): e1105. doi: 10.1038/cddis.2014.80.
32. Liu K, Yan L, Jiang X, et al. Acquired inhibition of microRNA-124 protects against spinal cord ischemia-reperfusion injury partially through a mitophagy-dependent pathway. J Thorac Cardiovasc Surg, 2017, 154(5): 1498-1508.
33. Li Q, Gao S, Kang Z, et al. Rapamycin enhances mitophagy and attenuates apoptosis after spinal ischemia-reperfusion injury. Front Neurosci, 2018, 12: 865. doi: 10.3389/fnins.2018.00865.
34. Neginskaya MA, Pavlov EV, Sheu SS. Electrophysiological properties of the mitochondrial permeability transition pores: Channel diversity and disease implication. Biochim Biophys Acta Bioenerg, 2021, 1862(3): 148357. doi: 10.1016/j.bbabio.2020.148357.
35. Wang S, Smith GM, Selzer ME, et al. Emerging molecular therapeutic targets for spinal cord injury. Expert Opin Ther Targets, 2019, 23(9): 787-803.
36. Springer JE, Visavadiya NP, Sullivan PG, et al. Post-injury treatment with NIM811 promotes recovery of function in adult female rats after spinal cord contusion: A dose-response study. J Neurotrauma, 2018, 35(3): 492-499.
37. Simmons EC, Scholpa NE, Schnellmann RG. FDA-approved 5-HT_1F receptor agonist lasmiditan induces mitochondrial biogenesis and enhances locomotor and blood-spinal cord barrier recovery after spinal cord injury. Exp Neurol, 2021, 341: 113720. doi: 10.1016/j.expneurol.2021.113720.
38. Simmons EC, Scholpa NE, Schnellmann RG. Mitochondrial biogenesis as a therapeutic target for traumatic and neurodegenerative CNS diseases. Exp Neurol, 2020, 329: 113309. doi: 10.1016/j.expneurol.2020.113309.
39. Cardanho-Ramos C, Morais VA. Mitochondrial biogenesis in neurons: How and where. Int J Mol Sci, 2021, 22(23): 13059. doi: 10.3390/ijms222313059.
40. Hu J, Lang Y, Zhang T, et al. Lentivirus-mediated PGC-1α overexpression protects against traumatic spinal cord injury in rats. Neuroscience, 2016, 328: 40-49.
41. Hu J, Lang Y, Cao Y, et al. The neuroprotective effect of tetramethylpyrazine against contusive spinal cord injury by activating PGC-1α in rats. Neurochem Res, 2015, 40(7): 1393-1401.
42. Scholpa NE, Williams H, Wang W, et al. Pharmacological stimulation of mitochondrial biogenesis using the food and drug administration-approved beta2-adrenoreceptor agonist formoterol for the treatment of spinal cord injury. J Neurotrauma, 2019, 36(6): 962-972.
43. Scholpa NE, Simmons EC, Crossman JD, et al. Time-to-treatment window and cross-sex potential of β₂-adrenergic receptor-induced mitochondrial biogenesis-mediated recovery after spinal cord injury. Toxicol Appl Pharmacol, 2021, 411: 115366. doi: 10.1016/j.taap.2020.115366.
44. Simmons EC, Scholpa NE, Cleveland KH, et al. 5-hydroxytryptamine 1F receptor agonist induces mitochondrial biogenesis and promotes recovery from spinal cord injury. J Pharmacol Exp Ther, 2020, 372(2): 216-223.

Chinese Journal of Reparative and Reconstructive Surgery

Advances of the role of mitochondrial dysfunction in the spinal cord injury and its relevant treatments

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