- Department of Neurology, the Second Affiliated Hospital of Chongqing Medical University, Chongqing 404100, China;
Epilepsy is a heterogeneous disease with a very complex etiological mechanism, characterized by recurrent and unpredictable abnormal neuronal discharge. Epilepsy patients mainly rely on oral antiseizure medication (ASMs) the for treatment and control of disease progression. However, about 30% patients are resistance to ASMs, leading to the inability to alleviate and cure seizures, which gradually evolve into refractory epilepsy. The most common type of intractable epilepsy is temporal lobe epilepsy. Therefore, in-depth exploration of the causes and molecular mechanisms of seizures is the key to find new methods for treating refractory epilepsy. Mitochondria are important organelles within cells, providing abundant energy to neurons and continuously driving their activity. Neurons rely on mitochondria for complex neurotransmitter transmission, synaptic plasticity processes, and the establishment of membrane excitability. The process by which the autophagy system degrades and metabolizes damaged mitochondria through lysosomes is called mitophagy. Mitophagy is a specific autophagic pathway that maintains cellular structure and function. Mitochondrial dysfunction can produce harmful reactive oxygen species, damage cell proteins and DNA, or trigger programmed cell death. Mitophagy helps maintain mitochondrial quality control and quantity regulation in various cell types, and is closely related to the occurrence and development of epilepsy. The imbalance of mitophagy regulation is one of the causes of abnormal neuronal discharge and epileptic seizures. Understanding its related mechanisms is crucial for the treatment and control of the progression of epilepsy in patients.
Citation: GAO Yuan, CHEN Yangmei. Research progress on mitophagy in epilepsy. Journal of Epilepsy, 2024, 10(4): 320-327. doi: 10.7507/2096-0247.202404006 Copy
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- 2. Thijs RD, Surges R, O'brien TJ, et al. Epilepsy in adults. The Lancet, 2019, 393(10172): 689-701.
- 3. Song P, Liu Y, Yu X, et al. Prevalence of epilepsy in China between 1990 and 2015: a systematic review and meta–analysis. Journal of global health, 2017, 7(2).
- 4. Ding D, Zhou D, Sander J W, et al. Epilepsy in China: major progress in the past two decades. The Lancet Neurology, 2021, 20(4): 316-326.
- 5. Vinti V, Dell'isola GB, Tascini G, et al. Temporal lobe epilepsy and psychiatric comorbidity. Frontiers in neurology, 2021, 12: 775781.
- 6. Petrilla AA, Sutton BS, Leinwand BI, et al. Incremental burden of mental health conditions in adult patients with focal seizures. Epilepsy & Behavior, 2020, 112: 107426.
- 7. Baev AY, Vinokurov AY, Novikova IN, et al. Interaction of mitochondrial calcium and ROS in neurodegeneration. Cells, 2022, 11(4): 706.
- 8. Datta S, Jaiswal M. Mitochondrial calcium at the synapse. Mitochondrion, 2021, 59: 135-153.
- 9. Devine MJ, Kittler JT. Mitochondria at the neuronal presynapse in health and disease. Nature Reviews Neuroscience, 2018, 19(2): 63-80.
- 10. Harrington JS, Ryter SW, Plataki M, et al. Mitochondria in health, disease, and aging. Physiological reviews, 2023, 103(4): 2349-2422.
- 11. Głombik K, Detka J, Budziszewska B. Hormonal regulation of oxidative phosphorylation in the brain in health and disease. Cells, 2021, 10(11): 2937.
- 12. Li S, Sheng ZH. Energy matters: presynaptic metabolism and the maintenance of synaptic transmission. Nature Reviews Neuroscience, 2022, 23(1): 4-22.
- 13. Tashiro R, Bautista-Garrido J, Ozaki D, et al. Transplantation of astrocytic mitochondria modulates neuronal antioxidant defense and neuroplasticity and promotes functional recovery after intracerebral hemorrhage. Journal of Neuroscience, 2022, 42(36): 7001-7014.
- 14. Onishi M, Yamano K, Sato M, et al. Molecular mechanisms and physiological functions of mitophagy. The EMBO journal, 2021, 40(3): e104705.
- 15. Schofield JH, Schafer ZT. Mitochondrial reactive oxygen species and mitophagy: a complex and nuanced relationship. Antioxidants & redox signaling, 2021, 34(7): 517-530.
- 16. Li S, Zhang J, Liu C, et al. The role of mitophagy in regulating cell death. Oxidative Medicine and Cellular Longevity, 2021, 2021.
- 17. Faas M, De Vos P. Mitochondrial function in immune cells in health and disease. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease, 2020, 1866(10): 165845.
- 18. Bussi C, Heunis T, Pellegrino E, et al. Lysosomal damage drives mitochondrial proteome remodelling and reprograms macrophage immunometabolism. Nature Communications, 2022, 13(1): 7338.
- 19. Zorov DB, Andrianova NV, Babenko VA, et al. Neuroprotective potential of mild uncoupling in mitochondria. Pros and cons. Brain Sciences, 2021, 11(8): 1050.
- 20. Evans CS, Holzbaur EL. Autophagy and mitophagy in ALS. Neurobiology of disease, 2019, 122: 35-40.
- 21. Wang Y, Liu N, Lu B. Mechanisms and roles of mitophagy in neurodegenerative diseases. CNS neuroscience & therapeutics, 2019, 25(7): 859-875.
- 22. Fritsch LE, Moore ME, Sarraf SA, et al. Ubiquitin and receptor-dependent mitophagy pathways and their implication in neurodegeneration. Journal of molecular biology, 2020, 432(8): 2510-2524.
- 23. Barazzuol L, Giamogante F, Brini M, et al. PINK1/parkin mediated mitophagy, Ca2+ signalling, and ER–mitochondria contacts in Parkinson’s disease. International journal of molecular sciences, 2020, 21(5): 1772.
- 24. Meyer JN, Leuthner TC, Luz AL. Mitochondrial fusion, fission, and mitochondrial toxicity. Toxicology, 2017, 391: 42-53.
- 25. Do HA, Baek KH. Cellular functions regulated by deubiquitinating enzymes in neurodegenerative diseases. Ageing Research Reviews, 2021, 69: 101367.
- 26. Zhang Y, Chen Z, Lin J, et al. The ubiquitin ligase E6AP facilitates HDAC6-mediated deacetylation and degradation of tumor suppressors. Signal Transduction and Targeted Therapy, 2020, 5(1): 243.
- 27. Kalinski AL, Kar AN, Craver J, et al. Deacetylation of Miro1 by HDAC6 blocks mitochondrial transport and mediates axon growth inhibition. Journal of Cell Biology, 2019, 218(6): 1871-1890.
- 28. Bader V, Winklhofer K F. PINK1 and Parkin: team players in stress-induced mitophagy. Biological Chemistry, 2020, 401(6-7): 891-899.
- 29. Mizushima N. The ATG conjugation systems in autophagy. Current opinion in cell biology, 2020, 63: 1-10.
- 30. Shu X, Sun Y, Sun X, et al. The effect of fluoxetine on astrocyte autophagy flux and injured mitochondria clearance in a mouse model of depression. Cell death & disease, 2019, 10(8): 577.
- 31. Miller S, Muqit MM. Therapeutic approaches to enhance PINK1/Parkin mediated mitophagy for the treatment of Parkinson’s disease. Neuroscience letters, 2019, 705: 7-13.
- 32. Lystad AH, Simonsen A. Mechanisms and pathophysiological roles of the ATG8 conjugation machinery. Cells, 2019, 8(9): 973.
- 33. Doblado L, Lueck C, Rey C, et al. Mitophagy in Human Diseases. International Journal of Molecular Sciences, 2021, 22(8): 3903.
- 34. Yamashita SI, Sugiura Y, Matsuoka Y, et al. Mitophagy mediated by BNIP3 and NIX protects against ferroptosis by downregulating mitochondrial reactive oxygen species. Cell Death & Differentiation, 2024: 1-11.
- 35. Marinković M, Novak I. A brief overview of BNIP3L/NIX receptor‐mediated mitophagy. FEBS open bio, 2021, 11(12): 3230-3236.
- 36. Wu X, Zheng Y, Liu M, et al. BNIP3L/NIX degradation leads to mitophagy deficiency in ischemic brains. Autophagy, 2021, 17(8): 1934-1946.
- 37. Li Y, Zheng W, Lu Y, et al. BNIP3L/NIX-mediated mitophagy: molecular mechanisms and implications for human disease. Cell Death & Disease, 2021, 13(1): 14.
- 38. Williams JA, Ding WX. Mechanisms, pathophysiological roles and methods for analyzing mitophagy–recent insights. Biological chemistry, 2018, 399(2): 147-178.
- 39. Chen G, Kroemer G, Kepp O. Mitophagy: an emerging role in aging and age-associated diseases. Frontiers in cell and developmental biology, 2020, 8: 200.
- 40. Malpartida AB, Williamson M, Narendra DP, et al. Mitochondrial dysfunction and mitophagy in Parkinson’s disease: from mechanism to therapy. Trends in biochemical sciences, 2021, 46(4): 329-343.
- 41. Wang R, Wang G. Autophagy in mitochondrial quality control. Autophagy: Biology and Diseases: Basic Science, 2019: 421-434.
- 42. Liang MZ, Ke TL, Chen L. Mitochondrial protein PGAM5 emerges as a new regulator in neurological diseases. Frontiers in Molecular Neuroscience, 2021, 14: 730604.
- 43. Liu L, Feng D, Chen G, et al. Mitochondrial outer-membrane protein FUNDC1 mediates hypoxia-induced mitophagy in mammalian cells. Nature cell biology, 2012, 14(2): 177-85.
- 44. Li Q, Han Y, Du J, et al. Alterations of apoptosis and autophagy in developing brain of rats with epilepsy: Changes in LC3, P62, Beclin-1 and Bcl-2 levels. Neuroscience research, 2018, 130: 47-55.
- 45. Wu M, Liu X, Chi X, et al. Mitophagy in refractory temporal lobe epilepsy patients with hippocampal sclerosis. Cellular and Molecular Neurobiology, 2018, 38: 479-486.
- 46. Zhong F, Gan Y, Song J, et al. The inhibition of PGAM5 suppresses seizures in a kainate-induced epilepsy model via mitophagy reduction. Frontiers in Molecular Neuroscience, 2022, 15: 1047801.
- 47. Zhang Y, Lian Y, Lian X, et al. FUNDC1 Mediated Mitophagy in Epileptic Hippocampal Neuronal Injury Induced by Magnesium-Free Fluid. Neurochemical Research, 2023, 48(1): 284-294.
- 48. Madireddy S, Madireddy S. Therapeutic strategies to ameliorate neuronal damage in epilepsy by regulating oxidative stress, mitochondrial dysfunction, and neuroinflammation. Brain Sciences, 2023, 13(5): 784.
- 49. Sun H, Li X, Guo Q, et al. Research progress on oxidative stress regulating different types of neuronal death caused by epileptic seizures. Neurological Sciences, 2022, 43(11): 6279-6298.
- 50. Yang N, Guan QW, Chen FH, et al. Antioxidants targeting mitochondrial oxidative stress: promising neuroprotectants for epilepsy. Oxidative Medicine and Cellular Longevity, 2020, 25: 6687185.
- 51. Peng Y, Chen L, Qu Y, et al. Rosiglitazone prevents autophagy by regulating Nrf2-antioxidant response element in a rat model of lithium-pilocarpine-induced status epilepticus. Neuroscience, 2021, 455: 212-222.
- 52. Han S, Zhang M, Jeong YY, et al. The role of mitophagy in the regulation of mitochondrial energetic status in neurons. Autophagy, 2021, 17(12): 4182-4201.
- 53. Singh S, Singh TG, Rehni AK, et al. Reviving mitochondrial bioenergetics: a relevant approach in epilepsy. Mitochondrion, 2021, 58: 213-226.
- 54. Limanaqi F, Biagioni F, Busceti CL, et al. mTOR-related cell-clearing systems in epileptic seizures, an update. International Journal of Molecular Sciences, 2020, 21(5): 1642.
- 55. Sumitomo A, Tomoda T. Autophagy in neuronal physiology and disease. Current Opinion in Pharmacology, 2021, 60: 133-140.
- 56. Chiareli RA, Carvalho GA, Marques BL, et al. The role of astrocytes in the neurorepair process. Frontiers in cell and developmental biology, 2021, 9: 665795.
- 57. Lampinen R, Belaya I, Boccuni I, et al. KM Mitochondrial function in Alzheimer’s disease: focus on astrocytes. Astrocyte Physiol. Pathol, 2017, 10.
- 58. Litwiniuk A, Juszczak GR, Stankiewicz AM, et al. The role of glial autophagy in Alzheimer’s disease. Molecular Psychiatry, 2023: 1-12.
- 59. Booth HD, Hirst WD, Wade-Martins R. The role of astrocyte dysfunction in Parkinson’s disease pathogenesis. Trends in neurosciences, 2017, 40(6): 358-370.
- 60. Bantle CM, Hirst WD, Weihofen A, et al. Mitochondrial dysfunction in astrocytes: a role in Parkinson’s disease?. Frontiers in Cell and Developmental Biology, 2021, 8: 608026.
- 61. Vezzani A, Ravizza T, Bedner P, et al. Astrocytes in the initiation and progression of epilepsy. Nature Reviews Neurology, 2022, 18(12): 707-722.
- 62. Saha S, Mahapatra K K, Mishra S R, et al. Bacopa monnieri inhibits apoptosis and senescence through mitophagy in human astrocytes. Food and Chemical Toxicology, 2020, 141: 111367.
- 63. Alam MM, Zhao XF, Liao Y, et al. Deficiency of microglial autophagy increases the density of oligodendrocytes and susceptibility to severe forms of seizures. Eneuro, 2021, 8(1).
- 64. Zhang S, Hu L, Jiang J, et al. HMGB1/RAGE axis mediates stress-induced RVLM neuroinflammation in mice via impairing mitophagy flux in microglia. Journal of Neuroinflammation, 2020, 17: 1-20.
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