Skip to content
2000
image of Recent Progress in Hydrogen-mediated Neuroprotection via Modulation of Mitochondrial Quality Control Mechanisms in Brain Injury

Abstract

Brain injury is a leading cause of mortality and long-term disability worldwide, characterized by energy metabolism dysfunction, oxidative stress, inflammatory responses, and programmed cell death, with mitochondrial dysfunction serving as a central pathological nexus. In recent years, hydrogen, as an emerging gaseous signaling molecule, has demonstrated remarkable neuroprotective effects in various experimental models of brain injury owing to its unique biological properties, including selective antioxidant, anti-inflammatory, anti-apoptotic, and mitochondrial-protective activities. This review comprehensively summarizes the protective effects and underlying molecular mechanisms of hydrogen in ischemic stroke, traumatic brain injury, hypoxic-ischemic encephalopathy, intracerebral hemorrhage, subarachnoid hemorrhage, chronic cerebral hypoperfusion, and toxic encephalopathy. Special emphasis is placed on hydrogen's ability to modulate mitochondrial quality control networks, encompassing antioxidative membrane protection, precise regulation of mitophagy, remodeling of mitochondrial dynamics, and metabolic reprogramming, thereby improving neuronal survival and functional recovery. Moreover, this review has discussed current limitations, unresolved scientific questions, and major challenges, while proposing future directions, such as multi-omics integration, advanced structural biology investigations, innovative experimental model optimization, and systematic clinical translational research. Collectively, hydrogen holds great promise as a novel mitochondria-targeted neuroprotective strategy for brain injury, offering not only a solid theoretical foundation but also a potential personalized and precise therapeutic avenue for future clinical applications in neurological disorders.

© 2026 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/cnr/10.2174/0115672026430179251224095358
2026-01-19
2026-01-26

  • From This Site

    /content/journals/cnr/10.2174/0115672026430179251224095358
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. Zhang L. Wang H. Long non-coding RNA in CNS injuries: A new target for therapeutic intervention. Mol. Ther. Nucleic Acids 2019 17 754 766 10.1016/j.omtn.2019.07.013 31437654
    [Google Scholar]
  2. Xu Y. Jia B. Li J. Li Q. Luo C. The interplay between ferroptosis and neuroinflammation in central neurological disorders. Antioxidants 2024 13 4 395 10.3390/antiox13040395 38671843
    [Google Scholar]
  3. Yang H. Zhou Z. Liu Z. Chen J. Wang Y. Sirtuin-3: A potential target for treating several types of brain injury. Front. Cell Dev. Biol. 2023 11 1154831 10.3389/fcell.2023.1154831 37009480
    [Google Scholar]
  4. Lu D. Wang Y. Liu G. Armcx1 attenuates secondary brain injury in an experimental traumatic brain injury model in male mice by alleviating mitochondrial dysfunction and neuronal cell death. Neurobiol. Dis. 2023 184 106228 10.1016/j.nbd.2023.106228 37454781
    [Google Scholar]
  5. Song C. Zhao J. Hao J. Aminoprocalcitonin protects against hippocampal neuronal death via preserving oxidative phosphorylation in refractory status epilepticus. Cell Death Discov. 2023 9 1 144 10.1038/s41420‑023‑01445‑7 37142587
    [Google Scholar]
  6. Kwon E.J. Skalak M. Lo Bu R. Bhatia S.N. Neuron-targeted nanoparticle for sirna delivery to traumatic brain injuries. ACS Nano 2016 10 8 7926 7933 10.1021/acsnano.6b03858 27429164
    [Google Scholar]
  7. Buhlman L.M. Krishna G. Jones T.B. Thomas T.C. Drosophila as a model to explore secondary injury cascades after traumatic brain injury. Biomed. Pharmacother. 2021 142 112079 10.1016/j.biopha.2021.112079 34463269
    [Google Scholar]
  8. Fontaine C. Jacq G. Perier F. Holleville M. Legriel S. The role of secondary brain insults in status epilepticus: A systematic review. J. Clin. Med. 2020 9 8 2521 10.3390/jcm9082521 32764270
    [Google Scholar]
  9. Vekaria H.J. Talley Watts L. Lin A.L. Sullivan P.G. Targeting mitochondrial dysfunction in CNS injury using Methylene Blue: Still a magic bullet? Neurochem. Int. 2017 109 117 125 10.1016/j.neuint.2017.04.004 28396091
    [Google Scholar]
  10. Tozihi M. Shademan B. Yousefi H. Avci C.B. Nourazarian A. Dehghan G. Melatonin: A promising neuroprotective agent for cerebral ischemia-reperfusion injury. Front. Aging Neurosci. 2023 15 1227513 10.3389/fnagi.2023.1227513 37600520
    [Google Scholar]
  11. Bolte A.C. Lukens J.R. Neuroimmune cleanup crews in brain injury. Trends Immunol. 2021 42 6 480 494 10.1016/j.it.2021.04.003 33941486
    [Google Scholar]
  12. Zhao M. Yao Y. Du J. 6-Gingerol alleviates neonatal hypoxic-ischemic cerebral and white matter injury and contributes to functional recovery. Front. Pharmacol. 2021 12 707772 10.3389/fphar.2021.707772 34630084
    [Google Scholar]
  13. Strocchi A. Levitt M.D. Maintaining intestinal H2 balance: Credit the colonic bacteria. Gastroenterology 1992 102 4 1424 1426 10.1016/0016‑5085(92)90790‑6 1551553
    [Google Scholar]
  14. Ohsawa I. Ishikawa M. Takahashi K. Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nat. Med. 2007 13 6 688 694 10.1038/nm1577 17486089
    [Google Scholar]
  15. Ou L. Liu H. Shi X. Terminalia chebula Retz. aqueous extract inhibits the Helicobacter pylori-induced inflammatory response by regulating the inflammasome signaling and ER-stress pathway. J. Ethnopharmacol. 2024 320 117428 10.1016/j.jep.2023.117428 37981121
    [Google Scholar]
  16. Zhang X. Xie F. Ma S. Mitochondria: One of the vital hubs for molecular hydrogen’s biological functions. Front. Cell Dev. Biol. 2023 11 1283820 10.3389/fcell.2023.1283820 38020926
    [Google Scholar]
  17. Xu H. Qin W. Hu X. Lentivirus-mediated overexpression of OTULIN ameliorates microglia activation and neuroinflammation by depressing the activation of the NF-κB signaling pathway in cerebral ischemia/reperfusion rats. J. Neuroinflammation 2018 15 1 83 10.1186/s12974‑018‑1117‑5 29544517
    [Google Scholar]
  18. Xu H. Li J. Wang Z. Methylene blue attenuates neuroinflammation after subarachnoid hemorrhage in rats through the Akt/GSK-3β/MEF2D signaling pathway. Brain Behav. Immun. 2017 65 125 139 10.1016/j.bbi.2017.04.020 28457811
    [Google Scholar]
  19. Song J.H. Jia H.Y. Shao T.P. Liu Z.B. Zhao Y.P. Hydrogen gas post conditioning alleviates cognitive dysfunction and anxiety like behavior in a rat model of subarachnoid hemorrhage. Exp. Ther. Med. 2021 22 4 1121 10.3892/etm.2021.10555 34504575
    [Google Scholar]
  20. Ono H. Nishijima Y. Ohta S. Hydrogen Gas inhalation treatment in acute cerebral infarction: A randomized controlled clinical study on safety and neuroprotection. J. Stroke Cerebrovasc. Dis. 2017 26 11 2587 2594 10.1016/j.jstrokecerebrovasdis.2017.06.012 28669654
    [Google Scholar]
  21. Saengsin K. Sittiwangkul R. Chattipakorn S.C. Chattipakorn N. Hydrogen therapy as a potential therapeutic intervention in heart disease: From the past evidence to future application. Cell. Mol. Life Sci. 2023 80 6 174 10.1007/s00018‑023‑04818‑4 37269385
    [Google Scholar]
  22. Sun Q. Cai J. Zhou J. Hydrogen-rich saline reduces delayed neurologic sequelae in experimental carbon monoxide toxicity. Crit. Care Med. 2011 39 4 765 769 10.1097/CCM.0b013e318206bf44 21200321
    [Google Scholar]
  23. Li Y. Bing R. Liu M. Can molecular hydrogen supplementation reduce exercise-induced oxidative stress in healthy adults? A systematic review and meta-analysis. Front. Nutr. 2024 11 1328705 10.3389/fnut.2024.1328705 38590828
    [Google Scholar]
  24. Long Y. Ang Y. Chen W. Hydrogen alleviates impaired lung epithelial barrier in acute respiratory distress syndrome via inhibiting Drp1-mediated mitochondrial fission through the Trx1 pathway. Free Radic. Biol. Med. 2024 218 132 148 10.1016/j.freeradbiomed.2024.03.022 38554812
    [Google Scholar]
  25. Tian R. Hou Z. Hao S. Hydrogen-rich water attenuates brain damage and inflammation after traumatic brain injury in rats. Brain Res. 2016 1637 1 13 10.1016/j.brainres.2016.01.029 26826009
    [Google Scholar]
  26. Wu F. Liang T. Liu Y. Sun Y. Wang B. Hydrogen mitigates brain injury by prompting NEDD4-CX43- mediated mitophagy in traumatic brain injury. Exp. Neurol. 2024 379 114876 10.1016/j.expneurol.2024.114876 38942265
    [Google Scholar]
  27. Htun Y. Nakamura S. Kusaka T. Hydrogen and therapeutic gases for neonatal hypoxic–ischemic encephalopathy: Potential neuroprotective adjuncts in translational research. Pediatr. Res. 2021 89 4 753 759 10.1038/s41390‑020‑0998‑z 32505123
    [Google Scholar]
  28. Liu H. A clinical mini-review: Clinical use of local anesthetics in cancersurgeries. The Gazett Medical Sci 2020 1 3 30 10.46766/thegms.pharmaco.20072104
    [Google Scholar]
  29. Jin Z. Zhang W. Liu H. Potential therapeutic application of local anesthetics in cancer treatment. Recent Patents Anticancer Drug Discov. 2022 17 4 326 342 10.2174/1574892817666220119121204 35043766
    [Google Scholar]
  30. Rahman M.H. Bajgai J. Sharma S. Effects of hydrogen gas inhalation on community-dwelling adults of various ages: A single-arm, open-label, prospective clinical trial. Antioxidants 2023 12 6 1241 10.3390/antiox12061241 37371971
    [Google Scholar]
  31. Xie F. Jiang X. Yi Y. Different effects of hydrogen-rich water intake and hydrogen gas inhalation on gut microbiome and plasma metabolites of rats in health status. Sci. Rep. 2022 12 1 7231 10.1038/s41598‑022‑11091‑1 35508571
    [Google Scholar]
  32. Iida A. Nosaka N. Yumoto T. The clinical application of hydrogen as a medical treatment. Acta Med. Okayama 2016 70 5 331 337 [PMID: 27777424
    [Google Scholar]
  33. Cole A.R. Sperotto F. DiNardo J.A. Safety of prolonged inhalation of hydrogen gas in air in healthy adults. Crit. Care Explor. 2021 3 10 e543 10.1097/CCE.0000000000000543 34651133
    [Google Scholar]
  34. Jiang Z. Alamuri T.T. Yang D.L. Annarino T. Muir E.R. Duong T.Q. Optimized dose of hydrogen-enriched water with minocycline combination therapy in experimental ischemic stroke. Brain Res. 2025 1866 149940 10.1016/j.brainres.2025.149940 40935311
    [Google Scholar]
  35. Xu Z. Song R. Chen Z. Hydrogen generators-protected mesenchymal stem cells reverse articular redox imbalance-induced immune dysfunction for osteoarthritis treatment. Biomaterials 2025 320 123239 10.1016/j.biomaterials.2025.123239 40054376
    [Google Scholar]
  36. Yang M. He Y. Deng S. Mitochondrial quality control: A pathophysiological mechanism and therapeutic target for stroke. Front. Mol. Neurosci. 2022 14 786099 10.3389/fnmol.2021.786099 35153669
    [Google Scholar]
  37. Liu H. Karsidag M. Chhatwal K. Wang P. Tang T. Single-cell and bulk RNA sequencing analysis reveals CENPA as a potential biomarker and therapeutic target in cancers. PLoS One 2025 20 1 e0314745 10.1371/journal.pone.0314745 39820192
    [Google Scholar]
  38. Hillered L. Enblad P. Nonischemic energy metabolic crisis in acute brain injury. Crit. Care Med. 2008 36 10 2952 2953 10.1097/CCM.0b013e3181872178 18812809
    [Google Scholar]
  39. Shandra O. Winemiller A.R. Heithoff B.P. Repetitive diffuse mild traumatic brain injury causes an atypical astrocyte response and spontaneous recurrent seizures. J. Neurosci. 2019 39 10 1944 1963 10.1523/JNEUROSCI.1067‑18.2018 30665946
    [Google Scholar]
  40. Dumbuya J.S. Chen L. Wu J.Y. Wang B. The role of G-CSF neuroprotective effects in neonatal hypoxic-ischemic encephalopathy (HIE): Current status. J. Neuroinflammation 2021 18 1 55 10.1186/s12974‑021‑02084‑4 33612099
    [Google Scholar]
  41. Su Y. Zhang L. Zhou Y. Ding L. Li L. Wang Z. The progress of research on histone methylation in ischemic stroke pathogenesis. J. Physiol. Biochem. 2022 78 1 1 8 10.1007/s13105‑021‑00841‑w 34472033
    [Google Scholar]
  42. Wu L. Xiong X. Wu X. Targeting Oxidative stress and inflammation to prevent ischemia-reperfusion injury. Front. Mol. Neurosci. 2020 13 28 10.3389/fnmol.2020.00028 32194375
    [Google Scholar]
  43. Fukuda K. Asoh S. Ishikawa M. Yamamoto Y. Ohsawa I. Ohta S. Inhalation of hydrogen gas suppresses hepatic injury caused by ischemia/reperfusion through reducing oxidative stress. Biochem. Biophys. Res. Commun. 2007 361 3 670 674 10.1016/j.bbrc.2007.07.088 17673169
    [Google Scholar]
  44. Pan S. Wang B. Yu M. Hydrogen alleviates myocardial infarction by impeding apoptosis via ROS-mediated mitochondrial endogenous pathway. Free Radic. Res. 2025 59 3 226 238 10.1080/10715762.2025.2474014 40040521
    [Google Scholar]
  45. Diao M. Zhang S. Wu L. Hydrogen gas inhalation attenuates seawater instillation-induced acute lung injury via the Nrf2 pathway in rabbits. Inflammation 2016 39 6 2029 2039 10.1007/s10753‑016‑0440‑1 27596008
    [Google Scholar]
  46. Yu Y. Yang Y. Yang M. Wang C. Xie K. Yu Y. Hydrogen gas reduces HMGB1 release in lung tissues of septic mice in an Nrf2/HO-1-dependent pathway. Int. Immunopharmacol. 2019 69 11 18 10.1016/j.intimp.2019.01.022 30660872
    [Google Scholar]
  47. Shimada S. Wakayama K. Fukai M. Hydrogen gas ameliorates hepatic reperfusion injury after prolonged cold preservation in isolated perfused rat liver. Artif. Organs 2016 40 12 1128 1136 10.1111/aor.12710 27140066
    [Google Scholar]
  48. Cui Y. Meng S. Zhang N. High‐concentration hydrogen inhalation mitigates sepsis‐associated encephalopathy in mice by improving mitochondrial dynamics. CNS Neurosci. Ther. 2024 30 9 e70021 10.1111/cns.70021 39258790
    [Google Scholar]
  49. Chen H. Lin H. Dong B. Wang Y. Yu Y. Xie K. Hydrogen alleviates cell damage and acute lung injury in sepsis via PINK1/Parkin-mediated mitophagy. Inflamm. Res. 2021 70 8 915 930 10.1007/s00011‑021‑01481‑y 34244821
    [Google Scholar]
  50. Zhao Q. Xie F. Guo D. Hydrogen inhalation inhibits microglia activation and neuroinflammation in a rat model of traumatic brain injury. Brain Res. 2020 1748 147053 10.1016/j.brainres.2020.147053 32814064
    [Google Scholar]
  51. Luo S. Wu J. Qiu Y. Hydrogen promotes the effectiveness of bone mesenchymal stem cell transplantation in rats with spinal cord injury. Stem Cells Int. 2023 2023 1 14 10.1155/2023/8227382 37181828
    [Google Scholar]
  52. Terasaki Y. Terasaki M. Kanazawa S. Effect of H 2 treatment in a mouse model of rheumatoid arthritis‐associated interstitial lung disease. J. Cell. Mol. Med. 2019 23 10 7043 7053 10.1111/jcmm.14603 31424157
    [Google Scholar]
  53. Li D. Ai Y. Hydrogen saline suppresses neuronal cell apoptosis and inhibits the p38 mitogen-activated protein kinase-caspase-3 signaling pathway following cerebral ischemia-reperfusion injury. Mol. Med. Rep. 2017 16 4 5321 5325 10.3892/mmr.2017.7294 28849153
    [Google Scholar]
  54. Bai Y. Mi W. Meng X. Hydrogen alleviated cognitive impairment and blood‒brain barrier damage in sepsis-associated encephalopathy by regulating ABC efflux transporters in a PPARα-dependent manner. BMC Neurosci. 2023 24 1 37 10.1186/s12868‑023‑00795‑3 37474902
    [Google Scholar]
  55. Li J. Ruan S. Jia J. Hydrogen attenuates postoperative pain through Trx1/ASK1/MMP9 signaling pathway. J. Neuroinflammation 2023 20 1 22 10.1186/s12974‑022‑02670‑0 36737785
    [Google Scholar]
  56. Zhuang Z. Zhou M. You W. Hydrogen-rich saline alleviates early brain injury via reducing oxidative stress and brain edema following experimental subarachnoid hemorrhage in rabbits. BMC Neurosci. 2012 13 1 47 10.1186/1471‑2202‑13‑47 22587664
    [Google Scholar]
  57. Navabi S.P. Badreh F. Khombi Shooshtari M. Hajipour S. Moradi Vastegani S. Khoshnam S.E. Microglia-induced neuroinflammation in hippocampal neurogenesis following traumatic brain injury. Heliyon 2024 10 16 e35869 10.1016/j.heliyon.2024.e35869 39220913
    [Google Scholar]
  58. Chen W. Guo C. Feng H. Chen Y. Mitochondria: Novel mechanisms and therapeutic targets for secondary brain injury after intracerebral hemorrhage. Front. Aging Neurosci. 2021 12 615451 10.3389/fnagi.2020.615451 33584246
    [Google Scholar]
  59. Ji X. Tian Y. Xie K. Liu W. Qu Y. Fei Z. Protective effects of hydrogen-rich saline in a rat model of traumatic brain injury via reducing oxidative stress. J. Surg. Res. 2012 178 1 e9 e16 10.1016/j.jss.2011.12.038 22475349
    [Google Scholar]
  60. Liu L. Wang S. Jiang L. Molecular hydrogen mitigates traumatic brain injury-induced lung injury via NLRP3 inflammasome inhibition. BMC Chem. 2025 19 1 138 10.1186/s13065‑025‑01513‑2 40405232
    [Google Scholar]
  61. Fischer T.D. Hylin M.J. Zhao J. Moore A.N. Waxham M.N. Dash P.K. Altered mitochondrial dynamics and TBI pathophysiology. Front. Syst. Neurosci. 2016 10 29 10.3389/fnsys.2016.00029 27065821
    [Google Scholar]
  62. Xie K. Wang Y. Yin L. Hydrogen gas alleviates sepsis-induced brain injury by improving mitochondrial biogenesis through the activation of PGC-α in mice. Shock 2021 55 1 100 109 10.1097/SHK.0000000000001594 32590694
    [Google Scholar]
  63. Zhang C.S. Han Q. Song Z.W. Jia H.Y. Shao T.P. Chen Y.P. Hydrogen gas post conditioning attenuates early neuronal pyroptosis in a rat model of subarachnoid hemorrhage through the mitoK ATP signaling pathway. Exp. Ther. Med. 2021 22 2 836 10.3892/etm.2021.10268 34149882
    [Google Scholar]
  64. Poupon-Bejuit L. Rocha-Ferreira E. Thornton C. Hagberg H. Rahim A.A. Neuroprotective effects of diabetes drugs for the treatment of neonatal hypoxia-ischemia encephalopathy. Front. Cell. Neurosci. 2020 14 112 10.3389/fncel.2020.00112 32435185
    [Google Scholar]
  65. Yang M. Wang K. Liu B. Shen Y. Liu G. Hypoxic-ischemic encephalopathy: Pathogenesis and promising therapies. Mol. Neurobiol. 2025 62 2 2105 2122 10.1007/s12035‑024‑04398‑9 39073530
    [Google Scholar]
  66. Kong W. Lu C. Role of mitochondria in neonatal hypoxic-ischemic encephalopathy. Histol. Histopathol. 2024 39 8 991 1000 [PMID: 38314617
    [Google Scholar]
  67. Dong X. Luo S. Hu D. Gallic acid inhibits neuroinflammation and reduces neonatal hypoxic-ischemic brain damages. Front Pediatr. 2022 10 973256 10.3389/fped.2022.973256 36619526
    [Google Scholar]
  68. Nemeth J. Toth-Szuki V. Varga V. Kovacs V. Remzso G. Domoki F. Molecular hydrogen affords neuroprotection in a translational piglet model of hypoxic-ischemic encephalopathy. J. Physiol. Pharmacol. 2016 67 5 677 689 [PMID: 28011948
    [Google Scholar]
  69. Kirshner H. Schrag M. Management of intracerebral hemorrhage: Update and future therapies. Curr. Neurol. Neurosci. Rep. 2021 21 10 57 10.1007/s11910‑021‑01144‑9 34599652
    [Google Scholar]
  70. Li Z. Li M. Shi S.X. Brain transforms natural killer cells that exacerbate brain edema after intracerebral hemorrhage. J. Exp. Med. 2020 217 12 e20200213 10.1084/jem.20200213 32870258
    [Google Scholar]
  71. Wan Y. Holste K.G. Hua Y. Keep R.F. Xi G. Brain edema formation and therapy after intracerebral hemorrhage. Neurobiol. Dis. 2023 176 105948 10.1016/j.nbd.2022.105948 36481437
    [Google Scholar]
  72. Takeuchi S. Nagatani K. Otani N. Wada K. Mori K. Hydrogen does not exert neuroprotective effects or improve functional outcomes in rats after intracerebral hemorrhage. Turk Neurosurg. 2016 26 6 854 859 [PMID: 27801926
    [Google Scholar]
  73. Choi K.S. Kim H.J. Do S.H. Hwang S.J. Yi H.J. Neuroprotective effects of hydrogen inhalation in an experimental rat intracerebral hemorrhage model. Brain Res. Bull. 2018 142 122 128 10.1016/j.brainresbull.2018.07.006 30016724
    [Google Scholar]
  74. An P. Zhao X.C. Liu M.J. You Y.Q. Li J.Y. Gender-based differences in neuroprotective effects of hydrogen gas against intracerebral hemorrhage-induced depression. Neurochem. Int. 2022 153 105276 10.1016/j.neuint.2022.105276 34995727
    [Google Scholar]
  75. Manaenko A. Lekic T. Ma Q. Zhang J.H. Tang J. Hydrogen inhalation ameliorated mast cell-mediated brain injury after intracerebral hemorrhage in mice. Crit. Care Med. 2013 41 5 1266 1275 10.1097/CCM.0b013e31827711c9 23388512
    [Google Scholar]
  76. Li L. Hu B. Chen C. Role of mitochondrial damage during cardiac apoptosis in septic rats. Chin. Med. J. (Engl.) 2013 126 10 1860 1866 10.3760/cma.j.issn.0366‑6999.20130074 23673100
    [Google Scholar]
  77. Chen J. Li M. Liu Z. Wang Y. Xiong K. Molecular mechanisms of neuronal death in brain injury after subarachnoid hemorrhage. Front. Cell. Neurosci. 2022 16 1025708 10.3389/fncel.2022.1025708 36582214
    [Google Scholar]
  78. Tan J. Zhu H. Zeng Y. Li J. Zhao Y. Li M. Therapeutic potential of natural compounds in subarachnoid haemorrhage. Neuroscience 2024 546 118 142 10.1016/j.neuroscience.2024.03.032 38574799
    [Google Scholar]
  79. Jin K. Wu H. Lv T. Dai J. Zhang X. Jin Y. Ethyl pyruvate attenuates delayed experimental cerebral vasospasm following subarachnoid haemorrhage in rats: Possible role of JNK pathway. RSC Advances 2018 8 14 7726 7734 10.1039/C7RA10801J 35539121
    [Google Scholar]
  80. Zhuang K. Zuo Y.C. Sherchan P. Wang J.K. Yan X.X. Liu F. Hydrogen inhalation attenuates oxidative stress related endothelial cells injury after subarachnoid hemorrhage in rats. Front. Neurosci. 2020 13 1441 10.3389/fnins.2019.01441 32038143
    [Google Scholar]
  81. Tan J. Ma Y. Song R. Ye H. Su J. He Z. Phosphodiesterase 4 regulates pyroptosis in subarachnoid hemorrhage. Neural Regen. Res. 2025 21 10.4103/NRR.NRR‑D‑24‑01381
    [Google Scholar]
  82. Deng X. Wu Y. Hu Z. The mechanism of ferroptosis in early brain injury after subarachnoid hemorrhage. Front. Immunol. 2023 14 1191826 10.3389/fimmu.2023.1191826 37266433
    [Google Scholar]
  83. Bai J.C. Yang H.X. Zhan C.C. Zhao L.Q. Liu J.R. Yang W. Hydrogen alleviates right ventricular hypertrophy by inhibiting ferroptosis via restoration of the Nrf2/HO-1 signaling pathway. World J. Cardiol. 2025 17 6 104832 10.4330/wjc.v17.i6.104832 40575431
    [Google Scholar]
  84. Zhang X. Shi X. Wang J. Xu Z. He J. Enriched environment remedies cognitive dysfunctions and synaptic plasticity through NMDAR-Ca2+-Activin A circuit in chronic cerebral hypoperfusion rats. Aging (Albany NY) 2021 13 16 20748 20761 10.18632/aging.203462 34462377
    [Google Scholar]
  85. Kalaria R.N. Akinyemi R. Ihara M. Stroke injury, cognitive impairment and vascular dementia. Biochim. Biophys. Acta Mol. Basis Dis. 2016 1862 5 915 925 10.1016/j.bbadis.2016.01.015 26806700
    [Google Scholar]
  86. Dong F. Yan W. Meng Q. Ebselen alleviates white matter lesions and improves cognitive deficits by attenuating oxidative stress via Keap1/Nrf2 pathway in chronic cerebral hypoperfusion mice. Behav. Brain Res. 2023 448 114444 10.1016/j.bbr.2023.114444 37098387
    [Google Scholar]
  87. Lin T.K. Pai M.S. Yeh K.C. Hung C.F. Wang S.J. Hydrogen inhalation exerts anti-seizure effects by preventing oxidative stress and inflammation in the hippocampus in a rat model of kainic acid-induced seizures. Neurochem. Int. 2025 183 105925 10.1016/j.neuint.2024.105925 39725210
    [Google Scholar]
  88. Onasanwo S.A. Velagapudi R. El-Bakoush A. Olajide O.A. Inhibition of neuroinflammation in BV2 microglia by the biflavonoid kolaviron is dependent on the Nrf2/ARE antioxidant protective mechanism. Mol. Cell. Biochem. 2016 414 1-2 23 36 10.1007/s11010‑016‑2655‑8 26838169
    [Google Scholar]
  89. Deck L.M. Hunsaker L.A. Vander Jagt T.A. Whalen L.J. Royer R.E. Vander Jagt D.L. Activation of anti-oxidant Nrf2 signaling by enone analogues of curcumin. Eur. J. Med. Chem. 2018 143 854 865 10.1016/j.ejmech.2017.11.048 29223100
    [Google Scholar]
  90. Yamazaki Y. Shinohara M. Shinohara M. Selective loss of cortical endothelial tight junction proteins during Alzheimer’s disease progression. Brain 2019 142 4 1077 1092 10.1093/brain/awz011 30770921
    [Google Scholar]
  91. Yu Y. Feng J. Lian N. Hydrogen gas alleviates blood-brain barrier impairment and cognitive dysfunction of septic mice in an Nrf2-dependent pathway. Int. Immunopharmacol. 2020 85 106585 10.1016/j.intimp.2020.106585 32447221
    [Google Scholar]
  92. Peng Z-R. Huang Y-Q. Huang F.L. Yang A.L. Mechanism of delayed encephalopathy after acute carbon monoxide poisoning. Neural Regen. Res. 2020 15 12 2286 2295 10.4103/1673‑5374.284995 32594050
    [Google Scholar]
  93. Shen M. Zheng Y. Zhu K. Hydrogen gas protects against delayed encephalopathy after acute carbon monoxide poisoning in a rat model. Neurol. Res. 2020 42 1 22 30 10.1080/01616412.2019.1685064 31679470
    [Google Scholar]
  94. Shen M.H. Cai J.M. Sun Q. Neuroprotective effect of hydrogen-rich saline in acute carbon monoxide poisoning. CNS Neurosci. Ther. 2013 19 5 361 363 10.1111/cns.12094 23607699
    [Google Scholar]
  95. Wang W. Tian L. Li Y. Effects of hydrogen-rich saline on rats with acute carbon monoxide poisoning. J. Emerg. Med. 2013 44 1 107 115 10.1016/j.jemermed.2012.01.065 22897968
    [Google Scholar]
  96. Lee H.L. Chen C.L. Yeh S.T. Zweier J.L. Chen Y.R. Biphasic modulation of the mitochondrial electron transport chain in myocardial ischemia and reperfusion. Am. J. Physiol. Heart Circ. Physiol. 2012 302 7 H1410 H1422 10.1152/ajpheart.00731.2011 22268109
    [Google Scholar]
  97. Lin Y.J. Yu X.Z. Li Y.H. Yang L. Inhibition of the mitochondrial respiratory components (Complex I and Complex III) as stimuli to induce oxidative damage in Oryza sativa L. under thiocyanate exposure. Chemosphere 2020 243 125472 10.1016/j.chemosphere.2019.125472 31995896
    [Google Scholar]
  98. Kari S. Kandhavelu J. Murugesan A. Thiyagarajan R. Kidambi S. Kandhavelu M. Mitochondrial complex III bypass complex I to induce ROS in GPR17 signaling activation in GBM. Biomed. Pharmacother. 2023 162 114678 10.1016/j.biopha.2023.114678 37054539
    [Google Scholar]
  99. Guo Q. Kawahata I. Cheng A. Fatty acid-binding proteins 3 and 5 are involved in the initiation of mitochondrial damage in ischemic neurons. Redox Biol. 2023 59 102547 10.1016/j.redox.2022.102547 36481733
    [Google Scholar]
  100. Zhao R.Z. Wang X.B. Jiang S. Elevated ROS depress mitochondrial oxygen utilization efficiency in cardiomyocytes during acute hypoxia. Pflugers Arch. 2020 472 11 1619 1630 10.1007/s00424‑020‑02463‑5 32940783
    [Google Scholar]
  101. Hu Y. Xing S. Huang Y. Chen C. Shen D. Chen J. New tiaoxin recipe alleviates energy metabolism disorders in an APPswe/] PS1DE9 mouse model of alzheimer’s disease. Comb. Chem. High Throughput Screen. 2024 27 4 621 631 10.2174/1386207326666230428112358 37132137
    [Google Scholar]
  102. Heinonen T. Ciarlo E. Le Roy D. Roger T. Impact of the dual deletion of the mitochondrial sirtuins SIRT3 and SIRT5 on anti-microbial host defenses. Front. Immunol. 2019 10 2341 10.3389/fimmu.2019.02341 31632409
    [Google Scholar]
  103. Liu Y.J. McIntyre R.L. Janssens G.E. Houtkooper R.H. Mitochondrial fission and fusion: A dynamic role in aging and potential target for age-related disease. Mech. Ageing Dev. 2020 186 111212 10.1016/j.mad.2020.111212 32017944
    [Google Scholar]
  104. Chung C.L. Huang Y.H. Lin C.J. Therapeutic effect of mitochondrial division inhibitor-1 (Mdivi-1) on hyperglycemia-exacerbated early and delayed brain injuries after experimental subarachnoid hemorrhage. Int. J. Mol. Sci. 2022 23 13 6924 10.3390/ijms23136924 35805932
    [Google Scholar]
  105. Ji W.K. Chakrabarti R. Fan X. Schoenfeld L. Strack S. Higgs H.N. Receptor-mediated Drp1 oligomerization on endoplasmic reticulum. J. Cell Biol. 2017 216 12 4123 4139 10.1083/jcb.201610057 29158231
    [Google Scholar]
  106. Scorrano L. Opening the doors to cytochrome c: Changes in mitochondrial shape and apoptosis. Int. J. Biochem. Cell Biol. 2009 41 10 1875 1883 10.1016/j.biocel.2009.04.016 19393761
    [Google Scholar]
  107. Wang H. Feng Y. Lu H. Low-level cefepime exposure induces high-level resistance in environmental bacteria: Molecular mechanism and evolutionary dynamics. Environ. Sci. Technol. 2022 56 21 15074 15083 10.1021/acs.est.2c00793 35608924
    [Google Scholar]
  108. Lu H. NaV channels in cancers: Nonclassical roles. Glob J Cancer Ther 2020 6 5 28 32
    [Google Scholar]
  109. Liu H. Hamaia S.W. Dobson L. The voltage-gated sodium channel β3 subunit modulates C6 glioma cell motility independently of channel activity. Biochim. Biophys. Acta Mol. Basis Dis. 2025 1871 6 167844 10.1016/j.bbadis.2025.167844 40245999
    [Google Scholar]
  110. Song Y. Ren S. Chen X. Inhibition of MFN1 restores tamoxifen-induced apoptosis in resistant cells by disrupting aberrant mitochondrial fusion dynamics. Cancer Lett. 2024 590 216847 10.1016/j.canlet.2024.216847 38583647
    [Google Scholar]
  111. Kulkarni P.G. Balasubramanian N. Manjrekar R. Banerjee T. Sakharkar A. DNA methylation-mediated Mfn2 gene regulation in the brain: A role in brain trauma-induced mitochondrial dysfunction and memory deficits. Cell. Mol. Neurobiol. 2023 43 7 3479 3495 10.1007/s10571‑023‑01358‑0 37193907
    [Google Scholar]
  112. Burtscher M. Burtscher J. MFN2: Shaping mitochondria and cardiac adaptations to hypoxia. Acta Physiol. (Oxf.) 2023 239 2 e14026 10.1111/apha.14026 37548341
    [Google Scholar]
  113. Li L. Qi R. Zhang L. Potential biomarkers and targets of mitochondrial dynamics. Clin. Transl. Med. 2021 11 8 e529 10.1002/ctm2.529 34459143
    [Google Scholar]
  114. Wu M. Gu X. Ma Z. Mitochondrial Quality Control in Cerebral Ischemia–Reperfusion Injury. Mol. Neurobiol. 2021 58 10 5253 5271 10.1007/s12035‑021‑02494‑8 34275087
    [Google Scholar]
  115. Wu Y. Hu Q. Cheng H. Yu J. Gao L. Gao G. USP30 impairs mitochondrial quality control and aggravates oxidative damage after traumatic brain injury. Biochem. Biophys. Res. Commun. 2023 671 58 66 10.1016/j.bbrc.2023.05.069 37300943
    [Google Scholar]
  116. Yu Z. Wang H. Tang W. Mitochondrial Ca2+ oscillation induces mitophagy initiation through the PINK1-Parkin pathway. Cell Death Dis. 2021 12 7 632 10.1038/s41419‑021‑03913‑3 34148057
    [Google Scholar]
  117. Cui Y. Liu J. Song Y. Chen C. Shen Y. Xie K. High concentration hydrogen protects sepsis‐associated encephalopathy by enhancing pink1/parkin‐mediated mitophagy and inhibiting cGAS ‐ STING ‐ IRF3 Pathway. CNS Neurosci. Ther. 2025 31 2 e70305 10.1111/cns.70305 40016173
    [Google Scholar]
  118. Wu M. Lu G. Lao Y. Garciesculenxanthone B induces PINK1-Parkin-mediated mitophagy and prevents ischemia-reperfusion brain injury in mice. Acta Pharmacol. Sin. 2021 42 2 199 208 10.1038/s41401‑020‑0480‑9 32759963
    [Google Scholar]
  119. Yue Z. Dong H. Wang Y. Propofol prevents neuronal mtDNA deletion and cerebral damage due to ischemia/reperfusion injury in rats. Brain Res. 2015 1594 108 114 10.1016/j.brainres.2014.10.016 25451088
    [Google Scholar]
  120. Li L. Liu F. Feng C. Chen Z. Zhang N. Mao J. Role of mitochondrial dysfunction in kidney disease: Insights from the cGAS-STING signaling pathway. Chin. Med. J. (Engl.) 2024 137 9 1044 1053 10.1097/CM9.0000000000003022 38445370
    [Google Scholar]
  121. Jing R. Hu Z.K. Lin F. Mitophagy-mediated mtDNA release aggravates stretching-induced inflammation and lung epithelial cell injury via the TLR9/MyD88/NF-κB pathway. Front. Cell Dev. Biol. 2020 8 819 10.3389/fcell.2020.00819 33015037
    [Google Scholar]
  122. Ishihara G. Kawamoto K. Komori N. Ishibashi T. Molecular hydrogen suppresses superoxide generation in the mitochondrial complex I and reduced mitochondrial membrane potential. Biochem. Biophys. Res. Commun. 2020 522 4 965 970 10.1016/j.bbrc.2019.11.135 31810604
    [Google Scholar]
  123. Hall E.D. Andrus P.K. Yonkers P.A. Brain hydroxyl radical generation in acute experimental head injury. J. Neurochem. 1993 60 2 588 594 10.1111/j.1471‑4159.1993.tb03189.x 8380437
    [Google Scholar]
  124. Rauhala P. Khaldi A. Mohanakumar K.P. Chiueh C.C. Apparent role of hydroxyl radicals in oxidative brain injury induced by sodium nitroprusside. Free Radic. Biol. Med. 1998 24 7-8 1065 1073 10.1016/S0891‑5849(97)00386‑9 9626559
    [Google Scholar]
  125. Yang Y. Zhu Y. Xi X. Anti inflammatory and antitumor action of hydrogen via reactive oxygen species (Review). Oncol. Lett. 2018 16 3 2771 2776 10.3892/ol.2018.9023 30127861
    [Google Scholar]
  126. Duan L. Quan L. Zheng B. Inflation using hydrogen improves donor lung quality by regulating mitochondrial function during cold ischemia phase. BMC Pulm. Med. 2023 23 1 213 10.1186/s12890‑023‑02504‑6 37330482
    [Google Scholar]
  127. Wu X. Li X. Liu Y. Hydrogen exerts neuroprotective effects on OGD/R damaged neurons in rat hippocampal by protecting mitochondrial function via regulating mitophagy mediated by PINK1/Parkin signaling pathway. Brain Res. 2018 1698 89 98 10.1016/j.brainres.2018.06.028 29958907
    [Google Scholar]
  128. Li L. Liu T. Liu L. Effect of hydrogen-rich water on the Nrf2/ARE signaling pathway in rats with myocardial ischemia-reperfusion injury. J. Bioenerg. Biomembr. 2019 51 6 393 402 10.1007/s10863‑019‑09814‑7 31768722
    [Google Scholar]
  129. Luo M. Lu J. Li C. Hydrogen improves exercise endurance in rats by promoting mitochondrial biogenesis. Genomics 2022 114 6 110523 10.1016/j.ygeno.2022.110523 36423772
    [Google Scholar]
  130. Tian J. Mao Y. Liu D. Li T. Wang Y. Zhu C. Mitophagy in brain injuries: mechanisms, roles, and therapeutic potential. Mol. Neurobiol. 2025 62 8 10856 10868 10.1007/s12035‑025‑04936‑z 40237948
    [Google Scholar]
  131. Satoh Y. Araki Y. Kashitani M. Molecular hydrogen prevents social deficits and depression-like behaviors induced by low-intensity blast in mice. J. Neuropathol. Exp. Neurol. 2018 77 9 827 836 10.1093/jnen/nly060 30053086
    [Google Scholar]
  132. Yan M. Yu Y. Mao X. Hydrogen gas inhalation attenuates sepsis-induced liver injury in a FUNDC1-dependent manner. Int. Immunopharmacol. 2019 71 61 67 10.1016/j.intimp.2019.03.021 30877875
    [Google Scholar]
  133. Shen Y.L. Shi Y.Z. Chen G.G. TNF-α induces Drp1-mediated mitochondrial fragmentation during inflammatory cardiomyocyte injury. Int. J. Mol. Med. 2018 41 4 2317 2327 10.3892/ijmm.2018.3385 29336470
    [Google Scholar]
  134. Li R. Liu Y. Xie J. Sirt3 mediates the protective effect of hydrogen in inhibiting ROS-induced retinal senescence. Free Radic. Biol. Med. 2019 135 116 124 10.1016/j.freeradbiomed.2019.02.005 30735837
    [Google Scholar]
  135. Chen H. Guo Y. Zhang Z. Symbiotic algae-bacteria dressing for producing hydrogen to accelerate diabetic wound healing. Nano Lett. 2022 22 1 229 237 10.1021/acs.nanolett.1c03693 34928162
    [Google Scholar]
  136. Zhao L. Wang Y. Zhang G. Zhang T. Lou J. Liu J. L-arabinose elicits gut-derived hydrogen production and ameliorates metabolic syndrome in C57BL/6J mice on high-fat-diet. Nutrients 2019 11 12 3054 10.3390/nu11123054 31847305
    [Google Scholar]
  137. Xue J. Zhao M. Liu Y. Hydrogen inhalation ameliorates hepatic inflammation and modulates gut microbiota in rats with high-fat diet-induced non-alcoholic fatty liver disease. Eur. J. Pharmacol. 2023 947 175698 10.1016/j.ejphar.2023.175698 36997047
    [Google Scholar]
  138. Liu H. Wang P. CRISPR screening and cell line IC50 data reveal novel key genes for trametinib resistance. Clin. Exp. Med. 2024 25 1 21 10.1007/s10238‑024‑01538‑2 39708249
    [Google Scholar]
  139. Rasteh A.M. Liu H. Wang P. Pan-cancer genetic profiles of mitotic DNA integrity checkpoint protein kinases. Cancer Biomark. 2024 41 3-4 CBM240119 [PMID: 40095483
    [Google Scholar]
  140. Zheng M. Yu H. Xue Y. The protective effect of hydrogen-rich water on rats with type 2 diabetes mellitus. Mol. Cell. Biochem. 2021 476 8 3089 3097 10.1007/s11010‑021‑04145‑x 33830396
    [Google Scholar]
  141. Cenigaonandia-Campillo A. Serna-Blasco R. Gómez-Ocabo L. Vitamin C activates pyruvate dehydrogenase (PDH) targeting the mitochondrial tricarboxylic acid (TCA) cycle in hypoxic KRAS mutant colon cancer. Theranostics 2021 11 8 3595 3606 10.7150/thno.51265 33664850
    [Google Scholar]
  142. Amitani H. Asakawa A. Cheng K. Hydrogen improves glycemic control in type1 diabetic animal model by promoting glucose uptake into skeletal muscle. PLoS One 2013 8 1 e53913 10.1371/journal.pone.0053913 23326534
    [Google Scholar]
  143. Stram A.R. Payne R.M. Post-translational modifications in mitochondria: protein signaling in the powerhouse. Cell. Mol. Life Sci. 2016 73 21 4063 4073 10.1007/s00018‑016‑2280‑4 27233499
    [Google Scholar]
  144. Engen J.R. Komives E.A. Complementarity of hydrogen/deuterium exchange mass spectrometry and cryo-electron microscopy. Trends Biochem. Sci. 2020 45 10 906 918 10.1016/j.tibs.2020.05.005 32487353
    [Google Scholar]
  145. Patel D. Shetty S. Acha C. Microinstrumentation for brain organoids. Adv. Healthc. Mater. 2024 13 21 2302456 10.1002/adhm.202302456 38217546
    [Google Scholar]
  146. Teodoro J.S. Machado I.F. Castela A.C. Chenodeoxycholic acid has non-thermogenic, mitodynamic anti-obesity effects in an in vitro CRISPR/Cas9 model of bile acid receptor TGR5 knockdown. Int. J. Mol. Sci. 2021 22 21 11738 10.3390/ijms222111738 34769169
    [Google Scholar]
  147. Hengrui L. Toxic medicine used in Traditional Chinese Medicine for cancer treatment: Are ion channels involved? J. Tradit. Chin. Med. 2022 42 6 1019 1022 [PMID: 36378062
    [Google Scholar]
  148. Hengrui L. An example of toxic medicine used in Traditional Chinese Medicine for cancer treatment. J. Tradit. Chin. Med. 2023 43 2 209 210 [PMID: 36994507
    [Google Scholar]
  149. Liu H. Effect of traditional medicine on clinical cancer. Biomed. J. Sci. Tech. Res. 2020 30 4 30 10.26717/BJSTR.2020.30.004979
    [Google Scholar]
  150. Liu H.R. Harnessing traditional medicine and biomarker-driven approaches to counteract Trichostatin A-induced esophageal cancer progression. World J. Gastroenterol. 2025 31 20 106443 10.3748/wjg.v31.i20.106443 40495945
    [Google Scholar]
/content/journals/cnr/10.2174/0115672026430179251224095358
Loading
Recent Progress in Hydrogen-mediated Neuroprotection via Modulation of Mitochondrial Quality Control Mechanisms in Brain Injury
Bentham Science Publishers ; https://doi.org/10.2174/0115672026430179251224095358
/content/journals/cnr/10.2174/0115672026430179251224095358
/content/journals/cnr/10.2174/0115672026430179251224095358
Loading

Data & Media loading...


  • Article Type:     Review Article
Keywords: Hydrogen ; mitochondrial dynamics ; mitochondrial quality control ; brain injury ; neuroprotection ; mitophagy

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test