title: Increased phosphorylation of dynamin-related protein 1 and mitochondrial fission in okadaic acid-treated neurons.
abstract: Mitochondrial dysfunction is a prominent feature of neurodegenerative diseases and aging. A recent study showed that phosphorylation of dynamin-related protein 1 (Drp1) is increased in Alzheimer's disease (AD) brains compared to control brains, indicating that mitochondrial fission is increased in AD brains. Here, we showed that Drp1 phosphorylation and mitochondrial fission were also increased in rat cortical neurons treated with okadaic acid (OA), which inhibits protein phosphatase-2A (PP2A) and induces AD-like tau phosphorylation and neuronal death. Concurrent with this abnormal increase in mitochondrial fission, mitochondrial reactive oxygen species (ROS) were also increased, suggesting mitochondrial damage and detrimental effects on cell survival. Parkin, which is necessary for mitophagy of abnormal mitochondria and has been shown to be decreased in AD brains, and K48-linked polyubiquitin were also decreased in OA-treated neurons, suggesting that the mitophagic process required to degrade detrimental ROS-generating mitochondria is disabled. Collectively, our results demonstrate that abnormal mitochondrial fission, ROS generation, and inefficient mitophagy all occur in PP2A-inhibited neurons, as in AD brains, and suggest that this model could be used in developing inhibitors of mitochondrial fission or ROS generation.
authors.affiliation: Department of Anatomy and Cell Biology, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Mi-Hyang
authors.initials: MH
authors.lastname: Cho
authors.forename: Dong-Hou
authors.initials: DH
authors.lastname: Kim
authors.forename: Jung-Eun
authors.initials: JE
authors.lastname: Choi
authors.forename: Eun-Ju
authors.initials: EJ
authors.lastname: Chang
authors.lastname: Seung-Yongyoon
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D034281:Dynamins / Q000378:metabolism*; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D019319:Okadaic Acid / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D019319:Okadaic Acid; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; C519851:Dnm1l protein, rat; D034281:Dynamins