Research progress on mitochondrial dysfunction-mediated vascular cognitive impairment_West China Medical Journal

Authors：

DU Renfeng , LI Qinghua , PAN Danhong , LIN Yanping , YANG Hualan ,  LI Yunxia

Department of Neurology, Shanghai Pudong Hospital-Fudan University Pudong Medical Center, Shanghai 201399, P. R. China;

Corresponding author：

LI Yunxia, Email: doctorliyunxia@163.com

Keywords：

Mitochondria; vascular cognitive impairment; chronic cerebral hypoperfusion; oxidative stress

DOI：

10.7507/1002-0179.202411060

Video：

Export PDF Favorites Scan Get Citation

Abstract Full text Figures/Tables Video References Cited by

Vascular cognitive impairment (VCI), a syndrome induced by cerebrovascular disease and its risk factors, has become a major public health challenge worldwide. Especially in the context of an increasingly aging population, its impact is becoming more significant. In recent years, research has gradually revealed the crucial role of chronic cerebral hypoperfusion (CCH) in the occurrence and development of VCI. CCH leads to long-term ischemia and hypoxia in brain tissue, which seriously threatens mitochondrial function and triggers a series of problems such as mitochondrial oxidative stress, calcium homeostasis disturbance, dynamic abnormalities, autophagy dysregulation, and impaired biogenesis. These issues are extensively involved in the pathological process of VCI. This article provides an overview of the correlation between mitochondrial dysfunction and VCI under CCH conditions, aiming to explore new directions for the treatment of VCI.

1.	Rajeev V, Fann DY, Dinh QN, et al. Pathophysiology of blood brain barrier dysfunction during chronic cerebral hypoperfusion in vascular cognitive impairment. Theranostics, 2022, 12(4): 1639-1658.
2.	Xu W, Bai Q, Dong Q, et al. Blood-brain barrier dysfunction and the potential mechanisms in chronic cerebral hypoperfusion induced cognitive impairment. Front Cell Neurosci, 2022, 16: 870674.
3.	Rundek T, Tolea M, Ariko T, et al. Vascular cognitive impairment (VCI). Neurotherapeutics, 2022, 19(1): 68-88.
4.	Rajeev V, Chai YL, Poh L, et al. Chronic cerebral hypoperfusion: a critical feature in unravelling the etiology of vascular cognitive impairment. Acta Neuropathol Commun, 2023, 11(1): 93.
5.	Zong Y, Li H, Liao P, et al. Mitochondrial dysfunction: mechanisms and advances in therapy. Signal Transduct Target Ther, 2024, 9(1): 124.
6.	Garbincius JF, Elrod JW. Mitochondrial calcium exchange in physiology and disease. Physiol Rev, 2022, 102(2): 893-992.
7.	He Y, He T, Li H, et al. Deciphering mitochondrial dysfunction: pathophysiological mechanisms in vascular cognitive impairment. Biomed Pharmacother, 2024, 174: 116428.
8.	Liu X, Hussain R, Mehmood K, et al. Mitochondrial-endoplasmic reticulum communication-mediated oxidative stress and autophagy. Biomed Res Int, 2022, 2022: 6459585.
9.	Teleanu DM, Niculescu AG, Lungu II, et al. An overview of oxidative stress, neuroinflammation, and neurodegenerative diseases. Int J Mol Sci, 2022, 23(11): 5938.
10.	Ojo OB, Amoo ZA, Saliu IO, et al. Neurotherapeutic potential of kolaviron on neurotransmitter dysregulation, excitotoxicity, mitochondrial electron transport chain dysfunction and redox imbalance in 2-VO brain ischemia/reperfusion injury. Biomed Pharmacother, 2019, 111: 859-872.
11.	Xu T, Ding W, Ji X, et al. Oxidative stress in cell death and cardiovascular diseases. Oxid Med Cell Longev, 2019, 2019: 9030563.
12.	Hu Y, Zhang F, Ikonomovic M, et al. The Role of NRF2 in cerebrovascular protection: implications for vascular cognitive impairment and dementia (VCID). Int J Mol Sci, 2024, 25(7): 3833.
13.	Wang XR, Shi GX, Yang JW, et al. Acupuncture ameliorates cognitive impairment and hippocampus neuronal loss in experimental vascular dementia through Nrf2-mediated antioxidant response. Free Radic Biol Med, 2015, 89: 1077-1084.
14.	Zhang J, Xiao Y, Liu H, et al. Edaravone dexborneol alleviates neuroinflammation by reducing neuroglial cell proliferation and suppresses neuronal apoptosis/autophagy in vascular dementia rats. Neurochem Res, 2023, 48(10): 3113-3128.
15.	Park JH, Young Park H, Lee HS, et al. Effects of α-lipoic acid on chronic cerebrovascular hypoperfusion in an animal model of vascular dementia. Eur Rev Med Pharmacol Sci, 2019, 23(6): 2587-2595.
16.	Yang C, He Y, Ren S, et al. Hydrogen attenuates cognitive impairment in rat models of vascular dementia by inhibiting oxidative stress and NLRP3 inflammasome activation. Adv Healthc Mater, 2024, 13(20): e2400400.
17.	D'Angelo D, Vecellio Reane D, Raffaello A. Neither too much nor too little: mitochondrial calcium concentration as a balance between physiological and pathological conditions. Front Mol Biosci, 2023, 10: 1336416.
18.	Vais H, Payne R, Paudel U, et al. Coupled transmembrane mechanisms control MCU- mediated mitochondrial Ca²⁺ uptake. Proc Natl Acad Sci U S A, 2020, 117(35): 21731-21739.
19.	Yu SP, Jiang MQ, Shim SS, et al. Extrasynaptic NMDA receptors in acute and chronic excitotoxicity: implications for preventive treatments of ischemic stroke and late-onset Alzheimer’s disease. Mol Neurodegener, 2023, 18(1): 43.
20.	Bernardi P, Carraro M, Lippe G. The mitochondrial permeability transition: recent progress and open questions. FEBS J, 2022, 289(22): 7051-7074.
21.	France G, Volianskis R, Ingram R, et al. Differential regulation of STP, LTP and LTD by structurally diverse NMDA receptor subunit-specific positive allosteric modulators. Neuropharmacology, 2022, 202: 108840.
22.	McShane R, Westby MJ, Roberts E, et al. Memantine for dementia. Cochrane Database Syst Rev, 2019, 3(3): CD003154.
23.	Cho YD, Byoun HS, Park KH, et al. The impact of enteral nimodipine on endothelial cell apoptosis in an animal subarachnoid hemorrhage model. Neurocrit Care, 2024, 41(2): 608-618.
24.	Yang Z, Lange F, Xia Y, et al. Nimodipine protects vascular and cognitive function in an animal model of cerebral small vessel disease. Stroke, 2024, 55(7): 1914-1922.
25.	Yu R, Lendahl U, Nistér M, et al. Regulation of mammalian mitochondrial dynamics: opportunities and challenges. Front Endocrinol (Lausanne), 2020, 11: 374.
26.	Adebayo M, Singh S, Singh AP, et al. Mitochondrial fusion and fission: the fine-tune balance for cellular homeostasis. FASEB J, 2021, 35(6): e21620.
27.	Zhou X, Chen H, Wang L, et al. Mitochondrial dynamics: a potential therapeutic target for ischemic stroke. Front Aging Neurosci, 2021, 13: 721428.
28.	Kraus F, Roy K, Pucadyil TJ, et al. Function and regulation of the divisome for mitochondrial fission. Nature, 2021, 590(7844): 57-66.
29.	Zhu T, Dong S, Qin N, et al. Dl-3-n-butylphthalide attenuates cerebral ischemia/reperfusion injury in mice through AMPK-mediated mitochondrial fusion. Front Pharmacol, 2024, 15: 1357953.
30.	Zhou ZW, Ren X, Zheng LJ, et al. LncRNA NEAT1 ameliorate ischemic stroke via promoting Mfn2 expression through binding to Nova and activates Sirt3. Metab Brain Dis, 2022, 37(3): 653-664.
31.	Ouyang M, Zhang Q, Shu J, et al. Capsaicin ameliorates the loosening of mitochondria- associated endoplasmic reticulum membranes and improves cognitive function in rats with chronic cerebral hypoperfusion. Front Cell Neurosci, 2022, 16: 822702.
32.	Wang S, Long H, Hou L, et al. The mitophagy pathway and its implications in human diseases. Signal Transduct Target Ther, 2023, 8(1): 304.
33.	Lu Y, Li Z, Zhang S, et al. Cellular mitophagy: mechanism, roles in diseases and small molecule pharmacological regulation. Theranostics, 2023, 13(2): 736-766.
34.	Zhao Z, Xie L, Shi J, et al. Neuroprotective effect of zishen huoxue decoction treatment on vascular dementia by activating PINK1/Parkin mediated mitophagy in the hippocampal CA1 Region. J Ethnopharmacol, 2024, 319(Pt 1): 117172.
35.	Hu Z, Wen T, Hu K, et al. Transcutaneous electrical acupoint stimulation ameliorates cognitive function through PINK1/Parkin mediated mitophagy in VD rats. Evid Based Complement Alternat Med, 2022, 2022: 2810794.
36.	Xu L, Qu C, Liu Y, et al. The environmental enrichment ameliorates chronic cerebral hypoperfusion-induced cognitive impairment by activating autophagy signaling pathway and improving synaptic function in hippocampus. Brain Res Bull, 2023, 204: 110798.
37.	Wang N, He J, Pan C, et al. Resveratrol activates autophagy via the AKT/mTOR signaling pathway to improve cognitive dysfunction in rats with chronic cerebral hypoperfusion. Front Neurosci, 2019, 13: 859.
38.	Chen YX, Yang H, Wang DS, et al. Gastrodin relieves cognitive impairment by regulating autophagy via PI3K/AKT signaling pathway in vascular dementia. Biochem Biophys Res Commun, 2023, 671: 246-254.
39.	Mao Z, Tian L, Liu J, et al. Ligustilide ameliorates hippocampal neuronal injury after cerebral ischemia reperfusion through activating PINK1/Parkin-dependent mitophagy. Phytomedicine, 2022, 101: 154111.
40.	Yuan Y, Tian Y, Jiang H, et al. Mechanism of PGC-1α-mediated mitochondrial biogenesis in cerebral ischemia-reperfusion injury. Front Mol Neurosci, 2023, 16: 1224964.
41.	Shademan B, Avci CB, Karamad V, et al. The role of mitochondrial biogenesis in ischemic stroke. J Integr Neurosci, 2023, 22(4): 88.
42.	Cardanho-Ramos C, Morais VA. Mitochondrial biogenesis in neurons: how and where. Int J Mol Sci, 2021, 22(23): 13059.
43.	Gao J, Qian T, Wang W. CTRP3 activates the AMPK/SIRT1-PGC-1α pathway to protect mitochondrial biogenesis and functions in cerebral ischemic stroke. Neurochem Res, 2020, 45(12): 3045-3058.
44.	Wright DC, Geiger PC, Han DH, et al. Calcium induces increases in peroxisome proliferator-activated receptor gamma coactivator-1alpha and mitochondrial biogenesis by a pathway leading to p38 mitogen-activated protein kinase activation. J Biol Chem, 2007, 282(26): 18793-18799.
45.	Miwa S, Kashyap S, Chini E, et al. Mitochondrial dysfunction in cell senescence and aging. J Clin Invest, 2022, 132(13): e158447.
46.	Han B, Jiang W, Liu H, et al. Upregulation of neuronal PGC-1α ameliorates cognitive impairment induced by chronic cerebral hypoperfusion. Theranostics, 2020, 10(6): 2832-2848.
47.	Zhao Y, Zhang J, Zheng Y, et al. NAD⁺ improves cognitive function and reduces neuroinflammation by ameliorating mitochondrial damage and decreasing ROS production in chronic cerebral hypoperfusion models through Sirt1/PGC-1α pathway. J Neuroinflammation, 2021, 18(1): 207.
48.	Lu Y, Bu FQ, Wang F, et al. Recent advances on the molecular mechanisms of exercise- induced improvements of cognitive dysfunction. Transl Neurodegener, 2023, 12(1): 9.

1. Rajeev V, Fann DY, Dinh QN, et al. Pathophysiology of blood brain barrier dysfunction during chronic cerebral hypoperfusion in vascular cognitive impairment. Theranostics, 2022, 12(4): 1639-1658.
2. Xu W, Bai Q, Dong Q, et al. Blood-brain barrier dysfunction and the potential mechanisms in chronic cerebral hypoperfusion induced cognitive impairment. Front Cell Neurosci, 2022, 16: 870674.
3. Rundek T, Tolea M, Ariko T, et al. Vascular cognitive impairment (VCI). Neurotherapeutics, 2022, 19(1): 68-88.
4. Rajeev V, Chai YL, Poh L, et al. Chronic cerebral hypoperfusion: a critical feature in unravelling the etiology of vascular cognitive impairment. Acta Neuropathol Commun, 2023, 11(1): 93.
5. Zong Y, Li H, Liao P, et al. Mitochondrial dysfunction: mechanisms and advances in therapy. Signal Transduct Target Ther, 2024, 9(1): 124.
6. Garbincius JF, Elrod JW. Mitochondrial calcium exchange in physiology and disease. Physiol Rev, 2022, 102(2): 893-992.
7. He Y, He T, Li H, et al. Deciphering mitochondrial dysfunction: pathophysiological mechanisms in vascular cognitive impairment. Biomed Pharmacother, 2024, 174: 116428.
8. Liu X, Hussain R, Mehmood K, et al. Mitochondrial-endoplasmic reticulum communication-mediated oxidative stress and autophagy. Biomed Res Int, 2022, 2022: 6459585.
9. Teleanu DM, Niculescu AG, Lungu II, et al. An overview of oxidative stress, neuroinflammation, and neurodegenerative diseases. Int J Mol Sci, 2022, 23(11): 5938.
10. Ojo OB, Amoo ZA, Saliu IO, et al. Neurotherapeutic potential of kolaviron on neurotransmitter dysregulation, excitotoxicity, mitochondrial electron transport chain dysfunction and redox imbalance in 2-VO brain ischemia/reperfusion injury. Biomed Pharmacother, 2019, 111: 859-872.
11. Xu T, Ding W, Ji X, et al. Oxidative stress in cell death and cardiovascular diseases. Oxid Med Cell Longev, 2019, 2019: 9030563.
12. Hu Y, Zhang F, Ikonomovic M, et al. The Role of NRF2 in cerebrovascular protection: implications for vascular cognitive impairment and dementia (VCID). Int J Mol Sci, 2024, 25(7): 3833.
13. Wang XR, Shi GX, Yang JW, et al. Acupuncture ameliorates cognitive impairment and hippocampus neuronal loss in experimental vascular dementia through Nrf2-mediated antioxidant response. Free Radic Biol Med, 2015, 89: 1077-1084.
14. Zhang J, Xiao Y, Liu H, et al. Edaravone dexborneol alleviates neuroinflammation by reducing neuroglial cell proliferation and suppresses neuronal apoptosis/autophagy in vascular dementia rats. Neurochem Res, 2023, 48(10): 3113-3128.
15. Park JH, Young Park H, Lee HS, et al. Effects of α-lipoic acid on chronic cerebrovascular hypoperfusion in an animal model of vascular dementia. Eur Rev Med Pharmacol Sci, 2019, 23(6): 2587-2595.
16. Yang C, He Y, Ren S, et al. Hydrogen attenuates cognitive impairment in rat models of vascular dementia by inhibiting oxidative stress and NLRP3 inflammasome activation. Adv Healthc Mater, 2024, 13(20): e2400400.
17. D'Angelo D, Vecellio Reane D, Raffaello A. Neither too much nor too little: mitochondrial calcium concentration as a balance between physiological and pathological conditions. Front Mol Biosci, 2023, 10: 1336416.
18. Vais H, Payne R, Paudel U, et al. Coupled transmembrane mechanisms control MCU- mediated mitochondrial Ca²⁺ uptake. Proc Natl Acad Sci U S A, 2020, 117(35): 21731-21739.
19. Yu SP, Jiang MQ, Shim SS, et al. Extrasynaptic NMDA receptors in acute and chronic excitotoxicity: implications for preventive treatments of ischemic stroke and late-onset Alzheimer’s disease. Mol Neurodegener, 2023, 18(1): 43.
20. Bernardi P, Carraro M, Lippe G. The mitochondrial permeability transition: recent progress and open questions. FEBS J, 2022, 289(22): 7051-7074.
21. France G, Volianskis R, Ingram R, et al. Differential regulation of STP, LTP and LTD by structurally diverse NMDA receptor subunit-specific positive allosteric modulators. Neuropharmacology, 2022, 202: 108840.
22. McShane R, Westby MJ, Roberts E, et al. Memantine for dementia. Cochrane Database Syst Rev, 2019, 3(3): CD003154.
23. Cho YD, Byoun HS, Park KH, et al. The impact of enteral nimodipine on endothelial cell apoptosis in an animal subarachnoid hemorrhage model. Neurocrit Care, 2024, 41(2): 608-618.
24. Yang Z, Lange F, Xia Y, et al. Nimodipine protects vascular and cognitive function in an animal model of cerebral small vessel disease. Stroke, 2024, 55(7): 1914-1922.
25. Yu R, Lendahl U, Nistér M, et al. Regulation of mammalian mitochondrial dynamics: opportunities and challenges. Front Endocrinol (Lausanne), 2020, 11: 374.
26. Adebayo M, Singh S, Singh AP, et al. Mitochondrial fusion and fission: the fine-tune balance for cellular homeostasis. FASEB J, 2021, 35(6): e21620.
27. Zhou X, Chen H, Wang L, et al. Mitochondrial dynamics: a potential therapeutic target for ischemic stroke. Front Aging Neurosci, 2021, 13: 721428.
28. Kraus F, Roy K, Pucadyil TJ, et al. Function and regulation of the divisome for mitochondrial fission. Nature, 2021, 590(7844): 57-66.
29. Zhu T, Dong S, Qin N, et al. Dl-3-n-butylphthalide attenuates cerebral ischemia/reperfusion injury in mice through AMPK-mediated mitochondrial fusion. Front Pharmacol, 2024, 15: 1357953.
30. Zhou ZW, Ren X, Zheng LJ, et al. LncRNA NEAT1 ameliorate ischemic stroke via promoting Mfn2 expression through binding to Nova and activates Sirt3. Metab Brain Dis, 2022, 37(3): 653-664.
31. Ouyang M, Zhang Q, Shu J, et al. Capsaicin ameliorates the loosening of mitochondria- associated endoplasmic reticulum membranes and improves cognitive function in rats with chronic cerebral hypoperfusion. Front Cell Neurosci, 2022, 16: 822702.
32. Wang S, Long H, Hou L, et al. The mitophagy pathway and its implications in human diseases. Signal Transduct Target Ther, 2023, 8(1): 304.
33. Lu Y, Li Z, Zhang S, et al. Cellular mitophagy: mechanism, roles in diseases and small molecule pharmacological regulation. Theranostics, 2023, 13(2): 736-766.
34. Zhao Z, Xie L, Shi J, et al. Neuroprotective effect of zishen huoxue decoction treatment on vascular dementia by activating PINK1/Parkin mediated mitophagy in the hippocampal CA1 Region. J Ethnopharmacol, 2024, 319(Pt 1): 117172.
35. Hu Z, Wen T, Hu K, et al. Transcutaneous electrical acupoint stimulation ameliorates cognitive function through PINK1/Parkin mediated mitophagy in VD rats. Evid Based Complement Alternat Med, 2022, 2022: 2810794.
36. Xu L, Qu C, Liu Y, et al. The environmental enrichment ameliorates chronic cerebral hypoperfusion-induced cognitive impairment by activating autophagy signaling pathway and improving synaptic function in hippocampus. Brain Res Bull, 2023, 204: 110798.
37. Wang N, He J, Pan C, et al. Resveratrol activates autophagy via the AKT/mTOR signaling pathway to improve cognitive dysfunction in rats with chronic cerebral hypoperfusion. Front Neurosci, 2019, 13: 859.
38. Chen YX, Yang H, Wang DS, et al. Gastrodin relieves cognitive impairment by regulating autophagy via PI3K/AKT signaling pathway in vascular dementia. Biochem Biophys Res Commun, 2023, 671: 246-254.
39. Mao Z, Tian L, Liu J, et al. Ligustilide ameliorates hippocampal neuronal injury after cerebral ischemia reperfusion through activating PINK1/Parkin-dependent mitophagy. Phytomedicine, 2022, 101: 154111.
40. Yuan Y, Tian Y, Jiang H, et al. Mechanism of PGC-1α-mediated mitochondrial biogenesis in cerebral ischemia-reperfusion injury. Front Mol Neurosci, 2023, 16: 1224964.
41. Shademan B, Avci CB, Karamad V, et al. The role of mitochondrial biogenesis in ischemic stroke. J Integr Neurosci, 2023, 22(4): 88.
42. Cardanho-Ramos C, Morais VA. Mitochondrial biogenesis in neurons: how and where. Int J Mol Sci, 2021, 22(23): 13059.
43. Gao J, Qian T, Wang W. CTRP3 activates the AMPK/SIRT1-PGC-1α pathway to protect mitochondrial biogenesis and functions in cerebral ischemic stroke. Neurochem Res, 2020, 45(12): 3045-3058.
44. Wright DC, Geiger PC, Han DH, et al. Calcium induces increases in peroxisome proliferator-activated receptor gamma coactivator-1alpha and mitochondrial biogenesis by a pathway leading to p38 mitogen-activated protein kinase activation. J Biol Chem, 2007, 282(26): 18793-18799.
45. Miwa S, Kashyap S, Chini E, et al. Mitochondrial dysfunction in cell senescence and aging. J Clin Invest, 2022, 132(13): e158447.
46. Han B, Jiang W, Liu H, et al. Upregulation of neuronal PGC-1α ameliorates cognitive impairment induced by chronic cerebral hypoperfusion. Theranostics, 2020, 10(6): 2832-2848.
47. Zhao Y, Zhang J, Zheng Y, et al. NAD⁺ improves cognitive function and reduces neuroinflammation by ameliorating mitochondrial damage and decreasing ROS production in chronic cerebral hypoperfusion models through Sirt1/PGC-1α pathway. J Neuroinflammation, 2021, 18(1): 207.
48. Lu Y, Bu FQ, Wang F, et al. Recent advances on the molecular mechanisms of exercise- induced improvements of cognitive dysfunction. Transl Neurodegener, 2023, 12(1): 9.

West China Medical Journal

Latest ArticlesResearch progress on mitochondrial dysfunction-mediated vascular cognitive impairment

Abstract Full text Figures/Tables Video References Cited by

Format

Content