Mitochondrial fragmentation is involved in methamphetamine-induced cell death in rat hippocampal neural progenitor cells.
Methamphetamine (METH) induces neurodegeneration through damage and apoptosis of dopaminergic nerve terminals and striatal cells, presumably via cross-talk between the endoplasmic reticulum and mitochondria-dependent death cascades. However, the effects of METH on neural progenitor cells (NPC), an important reservoir for replacing neurons and glia during development and injury, remain elusive. Using a rat hippocampal NPC (rhNPC) culture, we characterized the METH-induced mitochondrial fragmentation, apoptosis, and its related signaling mechanism through immunocytochemistry, flow cytometry, and Western blotting. We observed that METH induced rhNPC mitochondrial fragmentation, apoptosis, and inhibited cell proliferation. The mitochondrial fission protein dynamin-related protein 1 (Drp1) and reactive oxygen species (ROS), but not calcium (Ca2+) influx, were involved in the regulation of METH-induced mitochondrial fragmentation. Furthermore, our results indicated that dysregulation of ROS contributed to the oligomerization and translocation of Drp1, resulting in mitochondrial fragmentation in rhNPC. Taken together, our data demonstrate that METH-mediated ROS generation results in the dysregulation of Drp1, which leads to mitochondrial fragmentation and subsequent apoptosis in rhNPC. This provides a potential mechanism for METH-related neurodegenerative disorders, and also provides insight into therapeutic strategies for the neurodegenerative effects of METH.
Tian
Changhai
C
The Laboratory of Neurotoxicology at the Center for Neurovirology & Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, Nebraska, USA.
Murrin
L Charles
LC
Zheng
Jialin C
JC
D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D003593:Cytoplasm / Q000378:metabolism; D015259:Dopamine Agents / Q000633:toxicity*; D034281:Dynamins / Q000235:genetics / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D006624:Hippocampus / Q000166:cytology* / Q000378:metabolism; D008694:Methamphetamine / Q000633:toxicity*; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism
D015259:Dopamine Agents; D008694:Methamphetamine; C519851:Dnm1l protein, rat; D034281:Dynamins