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The Western blot (WB) was used to compare the differences in Parkin protein expression between the epilepsy group and the control group. Immunofluorescence was used to detect the expression of MitoTracker and LysoTracker. Transferrin\u2010Alexa488 (Tf\u2010A488) was injected into the hippocampus of mice. We evaluated the effect of 3\u2010methyladenine (3\u2010MA) on epilepsy behavior through observation in PTZ\u2010kindled models.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The methylated derivative of adenine, known as 3\u2010MA, has been extensively utilized in the field of autophagy research. The transferrin protein is internalized from the extracellular environment into the intracellular space via the CME pathway. Tf\u2010A488 uses a fluorescent marker to track CME. Western blot showed that the expression of Parkin was significantly increased in the PTZ\u2010kindled model (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05), while 3\u2010MA could reduce the expression (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05). The fluorescence uptake of MitoTracker and LysoTracker was increased in the primary cultured neurons induced by magnesium\u2010free extracellular fluid (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05); the fluorescence uptake of Tf\u2010A488 was significantly decreased in the 3\u2010MA group compared with the control group (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05). Following hippocampal injection of Tf\u2010A488, both the epilepsy group and the 3\u2010MA group exhibited decreased fluorescence uptake, with a more pronounced effect observed in the 3\u2010MA group. Inhibition of mitophagy by 3\u2010MA from day 3 to day 9 progressively exacerbated seizure severity and shortened latency.<\/jats:p><\/jats:sec><jats:sec><jats:title>Significance<\/jats:title><jats:p>It is speculated that the aggravation of seizures by 3\u2010MA may be related to the failure to remove damaged mitochondria in time and effectively after inhibiting mitochondrial autophagy, affecting the vesicle endocytosis function of CME and increasing the susceptibility to epilepsy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Summary<\/jats:title><jats:p>Abnormal mitophagy was observed in a chronic pentylenetetrazol\u2010induced seizure model and a Mg<jats:sup>2+<\/jats:sup>\u2010free\u2010induced spontaneous recurrent epileptiform discharge model. A fluorescent transferrin marker was utilized to track clathrin\u2010mediated endocytosis. Using an autophagy inhibitor (3\u2010methyladenine) on primary cultured neurons, we discovered that inhibition of autophagy led to a reduction in fluorescent transferrin uptake, while impairing clathrin\u2010mediated endocytosis function mediated by mitophagy. Finally, we examined the effects of 3\u2010methyladenine in an animal model of seizures showing that it exacerbated seizure severity. Ultimately, this study provides insights into potential mechanisms through which mitophagy regulates clathrin\u2010mediated endocytosis in epilepsy.<\/jats:p><\/jats:sec>","DOI":"10.1002\/epi4.12945","type":"journal-article","created":{"date-parts":[[2024,5,3]],"date-time":"2024-05-03T12:19:55Z","timestamp":1714738795000},"page":"1252-1264","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["The mechanism of mitochondrial autophagy regulating Clathrin\u2010mediated endocytosis in epilepsy"],"prefix":"10.1002","volume":"9","author":[{"given":"Xuejiao","family":"Zhou","sequence":"first","affiliation":[{"name":"Department of Neurology The Affiliated Hospital of Zunyi Medical University  Zunyi China"},{"name":"The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Zunyi Medical University  Zunyi 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