Complex II inhibition by 3-NP causes mitochondrial fragmentation and neuronal cell death via an NMDA- and ROS-dependent pathway
Abbreviated Journal Title
Cell Death Differ.
mitochondria; Huntington's disease; nitric oxide; NMDA receptor; excitotoxicity; reactive oxygen species; TOXIN 3-NITROPROPIONIC ACID; HUNTINGTONS-DISEASE; MUTANT HUNTINGTIN; CORTICAL-NEURONS; NITRIC-OXIDE; ENERGY-METABOLISM; TRANSGENIC MOUSE; STRIATAL CELLS; DNA DAMAGE; IN-VIVO; Biochemistry & Molecular Biology; Cell Biology
Mitochondrial respiratory complex II inhibition plays a central role in Huntington's disease (HD). Remarkably, 3-NP, a complex II inhibitor, recapitulates HD-like symptoms. Furthermore, decreases in mitochondrial fusion or increases in mitochondrial fission have been implicated in neurodegenerative diseases. However, the relationship between mitochondrial energy defects and mitochondrial dynamics has never been explored in detail. In addition, the mechanism of neuronal cell death by complex II inhibition remains unclear. Here, we tested the temporal and spatial relationship between energy decline, impairment of mitochondrial dynamics, and neuronal cell death in response to 3-NP using quantitative fluorescence time-lapse microscopy and cortical neurons. 3-NP caused an immediate drop in ATP. This event corresponded with a mild rise in reactive oxygen species (ROS), but mitochondrial morphology remained unaltered. Unexpectedly, several hours after this initial phase, a second dramatic rise in ROS occurred, associated with profound mitochondrial fission characterized by the conversion of filamentous to punctate mitochondria and neuronal cell death. Glutamate receptor antagonist AP5 abolishes the second peak in ROS, mitochondrial fission, and cell death. Thus, secondary excitotoxicity, mediated by glutamate receptor activation of the NMDA subtype, and consequent oxidative and nitrosative stress cause mitochondrial fission, rather than energy deficits per se. These results improve our understanding of the cellular mechanisms underlying HD pathogenesis. Cell Death and Differentiation (2009) 16, 899-909; doi: 10.1038/cdd.2009.22; published online 20 March 2009
Cell Death and Differentiation
"Complex II inhibition by 3-NP causes mitochondrial fragmentation and neuronal cell death via an NMDA- and ROS-dependent pathway" (2009). Faculty Bibliography 2000s. 1806.