Huntington’s disease (HD) is a neurodegenerative disorder which is caused by a mutation in the Huntington’s gene (IT15). It has been found that changes in the cortex and striatum lead to motor, cognitive and emotional deficits in those suffering from HD. The mechanism that is responsible for neurodegeneration is not entirely clear, but it is known that degeneration of the neurons in the striatum in particular is the reason for many of these symptoms. In a study by Liot et al (2009) on how “Complex II inhibition by 3-NP causes mitochondrial fragmentation and neuronal cell death via an NMDA- and ROS- dependent pathway” occurs, some interesting data with regards to HD was revealed. By recreating the conditions thought to be present in mitochondrion of an individual with HD, researchers were able to analyze the altered stages of ATP production and the effects on neuronal cell vitality.
The underlying cause of HD is a lack of complex II or in the lab an inactivity of complex II within the mitochondrial matrix. In order to recreate these conditions researchers used 3-nitropropionic acid (3-NP), an irreversible inhibitor of succinate dehydrogenase, to block respiration and decrease levels of ATP causing changes in mitochondrial morphology. It was found that 3-NP not only decreases levels of ATP but also increases the level of reactive oxygen species (ROS) in two separate phases. Increased levels of ROS are responsible for mitochondrial fragmentation and subsequently cell death.
While the first rise in ROS seemed to be associated with the drop in ATP levels, the second rise is far more important in determining the cause of mitochondrial morphology and cell death. “Our results indicate that secondary excitotoxicity, rather than the initial 3-NP-induced bioenergetic deficits characterized by ATP drop and mild ROS increase, causes mitochondrial fission and neuronal cell death” (Liot et al). Subsequent tests were performed in an attempt to find a correlation between N-methyl-D-aspartate (NMDA) receptor activity and 3-NP-incuded punctate mitochondrial morphology using D-2-amino-5-phosphonopentanoate (AP5) on its own or in conjunction with 3-NP.
It was found that AP5 effectively antagonizes the NMDA receptor (subtype of glutamate) causing the morphology of the mitochondrion to remain tubular rather than punctate- which leads to cell death. These findings allow for a connection to be made between the second rise in ROS and NMDA receptor activation. More extensive tests revealed that certain antioxidants were found to reverse or block the mitochondrial fragmentation caused by 3-NP. Therefore specific free radicals may be the culprit behind the change from tubular to punctate mitochondrial morphology. “Results of this study suggest that mitochondrial fragmentation, complex II inhibition, NMDA receptor activation, and free radical production might contribute to HD-linked pathogenesis” (Liot et al). Although a decrease in ATP levels is one of the first effects of the huntingtin mutation, it is not the sole factor contributing to the fatality of Huntington’s disease. Similar to many other neurodegenerative disorders, this increase in the rate of mitochondrial fission plays a detrimental role in cell life.
Works Cited:
Liot, G., Bossy, B., Lubitz, S., Kushnareva, Y., Sejbuk, N., & Bossy-Wetzel, E. (2009).     Complex II inhibition by 3-NP causes mitochondrial fragmentation and neuronal cell death via an NMDA- and ROS-dependent pathway. Cell Death and Differentiation, 16(6), 899-909.