Mitochondrial Fragmentation Is Involved in Methamphetamine-Induced Cell Death in Rat Hippocampal Neural Progenitor Cells

Abstract

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.

Persistent disruption of mitochondrial homeostasis after acute kidney injury

“…Brooks et al (4) demonstrated that by inhibiting Drp1 either pharmacologically or by molecular techniques attenuated mitochondrial fragmentation, cytochrome c release, apoptosis, and kidney injury in both cellular and animal models of AKI. Both of the AKI models used in the current study are consistent with the results obtained by Brooks et al and others, which demonstrated induction of Drp1 is correlated with caspase 3 cleavage and apoptosis (11,19,32). However, the current study also demonstrates alterations in the mitochondrial fusion protein Mfn2 following AKI, and the contribution of this protein to mitochondrial fragmentation and injury progression has not been fully evaluated and warrants additional attention in future studies.…”

Parkin and Mitofusins Reciprocally Regulate Mitophagy and Mitochondrial Spheroid Formation

“…Depolarization and oxidative stress have been shown to inhibit mitochondrial fusion and/or to promote mitochondrial fragmentation (3,(27)(28)(29). Indeed, CCCP treatment led to mitochondrial fragmentation, which was not dependent on the autophagy machinery ( Fig.…”

Mitochondrial network in the heart

“…It regulates mitochondria number to match the metabolic or developmental demands. In addition, it removes the damaged mitochondria (Tolkovsky et al, 2002;Kundu et al, 2008). Pink1 and Parkin form an axis that regulates mitophagy in mammalian cells.…”

“…Knockdown of Drp1 delays the ROS production (Kobashigawa et al, 2011). Drp1 and ROS mediate the methamphetamine-induced mitochondrial fission (Tian et al, 2009). Mfn-1 remodels the outer mitochondrial membrane in mitochondrial fusion.…”