Cytochrome c oxidase mediates the regulation of mitochondrial function in an in vitro model of Huntington's disease

Mitochondrial dysfunction leading to neurodegenerative diseases involves structural and functional changes of respiratory chain enzyme complexes. The data shown here manifested the effect of 3-nitropropionic acid (NPA), a mitochondrial toxin and in vitro model of Huntington’s disease (HD), on mitochondrial regulation and function which adds another evidence for COX as a respiratory chain enzyme to be an important participant in a neurodegenerative disease. With respect to the potential role of COX in toxin-induced cell death and degenerative diseases, I particularly aimed to analyze the expression of the COX subunit IV isoform and related it to functional consequences for the survival of striatal astrocytes and neurons. Although it is well-known that NPA leads to an impairment of the cellular energy status, I found increased ATP levels in NPA-treated striatal astrocytes. This effect could be explained by an alteration of the expression pattern of COX subunit IV isoforms after 48 h of treatment of astrocytes with 10 mM NPA. The antidromic change caused by a switch of COX IV isoforms in striatal astrocytes led to a higher enzyme activity at the expense of a higher mitochondrial peroxide production. The resulting increased oxidative stress could, at least in part, explain the increased necrotic death of NPA-treated cells. The application of a siRNA-mediated knock-down system supported the causal link between the COX IV-2 expression and increased necrotic cell death due to elevated ROS production. The underlying mechanism of this regulatory process involves the binding of ATP to COX subunit IV-1 in the presence of a high ATP/ADP ratio, thereby causing an allosteric inhibition of COX, which is abolished by the expression of COX isoform IV-2. Overall, neurons showed a higher vulnerability towards NPA-mediated toxicity than astrocytes. Striatal but not cortical neurons demonstrated a similar chain of features and events beginning with increased transcription of COX isoform IV-2 accompanied by elevated ATP and ROS. In conclusion, I demonstrated the crucial role of COX isoform IV-2 for the development of oxidative stress after NPA treatment leading to elevated necrosis in astrocytes, which could affect proper astroglia function under pathological conditions and, in turn, indirectly contribute to reduction of neuronal survival. Along with this, the fact of different brain regions responding differently to toxic conditions was highlighted and could explain why striatal neurons are more prone to death under intoxication of NPA.

Grantor dc:publisher

Publikationsserver der RWTH Aachen University

Year dc:date

2009

Author dc:creator

• Singh, Shilpee

Contributors dc:contributor

• Wagner, Hermann

• info:eu-repo/classification/ddc/570
• Mitochondrium
• Cytochromoxidase
• Astrozyt
• Nervenzelle
• Huntington-Chorea
• Biowissenschaften, Biologie
• mitochondria
• neurons
• astrocytes
• Chorea Huntington
• cytochrom oxidase
• 3-nitropropionic acid

Statement dc:rights

• info:eu-repo/semantics/openAccess

Language dc:language

eng

Identifier

https://publications.rwth-aachen.de/search?p=id:%22RWTH-CONV-113671%22

OAI record oai:identifier

https://publications.rwth-aachen.de/oai2d?verb=GetRecord&metadataPrefix=oai_dc&identifier=oai%3Apublications.rwth-aachen.de%3A51370