Bid mediates fission, membrane permeabilization and peri-nuclear accumulation of mitochondria as a prerequisite for oxidative neuronal cell death.
Mitochondria are highly dynamic organelles that undergo permanent fusion and fission, a process that is important for mitochondrial function and cellular survival. Emerging evidence suggests that oxidative stress disturbs mitochondrial morphology dynamics, resulting in detrimental mitochondrial fragmentation. In particular, such fatal mitochondrial fission has been detected in neurons exposed to oxidative stress, suggesting mitochondrial dynamics as a key feature in intrinsic death pathways. However, the regulation of mitochondrial fission in neurons exposed to lethal stress is largely unknown. Here, we used a model of glutamate toxicity in HT-22 cells for investigating mitochondrial fission and fusion in neurons exposed to oxidative stress. In these immortalized hippocampal neurons, glutamate induces glutathione depletion and increased formation of reactive oxygen species (ROS). Glutamate toxicity resulted in mitochondrial fragmentation and peri-nuclear accumulation of the organelles. Further, mitochondrial fission was associated with loss of mitochondrial outer membrane potential (MOMP). The Bid-inhibitor BI-6c9 prevented MOMP and mitochondrial fission, and protected the cells from cell death. In conclusion, oxidative stress induced by glutamate causes mitochondrial translocation of Bid thereby inducing mitochondrial fission and associated mitochondrial cell death pathways. Inhibiting regulators of pathological mitochondrial fragmentation is proposed as an efficient strategy of neuroprotection.
Grohm
Julia
J
Institut für Pharmakologie und Klinische Pharmazie, Fachbereich Pharmazie, Philipps-Universität Marburg, Marburg, Germany.
Plesnila
Nikolaus
N
Culmsee
Carsten
C
D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism*; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D018014:Gene Transfer Techniques; D018698:Glutamic Acid / Q000378:metabolism / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007150:Immunohistochemistry; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism
D051023:BH3 Interacting Domain Death Agonist Protein; D017382:Reactive Oxygen Species; D018698:Glutamic Acid