Cytochrome c oxidase isoform IV-2 is involved in 3-nitropropionic acid-induced toxicity in striatal astrocytes.
Astrocyte mitochondria play an important role for energy supply and neuronal survival in the brain. Toxic and degenerative processes are largely associated with mitochondrial dysfunction. We, therefore, investigated the effect of 3-nitropropionic acid (NPA), a mitochondrial toxin and in vitro model of Huntington's disease (HD), on mitochondrial function and viability of primary striatal astrocytes. Although NPA is known as an irreversible inhibitor of succinate dehydrogenase, we observed an increase of astrocyte ATP levels after NPA treatment. This effect could be explained by NPA-mediated alterations of cytochrome c oxidase subunit IV isoform (COX IV) expression. The up-regulation of COX isoform IV-2 caused an increased enzyme activity at the expense of elevated mitochondrial peroxide production causing increased cell death. The application of a small interfering RNA against COX IV-2 revealed the causal implication of COX isoform IV-2 in NPA-mediated elevation of oxidative stress and necrotic cell death. Thus, we propose a novel, additional mechanism of NPA-induced cell stress and death which is based on structural and functional changes of astrocyte COX and which could indirectly impair neuronal survival.
Singh
Shilpee
S
Institute for Neuroanatomy, Faculty of Medicine, RWTH Aachen University, Aachen, Germany.
Misiak
Magdalena
M
Beyer
Cordian
C
Arnold
Susanne
S
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D003576:Electron Transport Complex IV / Q000378:metabolism*; D006816:Huntington Disease; D007527:Isoenzymes / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D009336:Necrosis / Q000139:chemically induced / Q000503:physiopathology; D009498:Neurotoxins / Q000633:toxicity*; D009574:Nitro Compounds / Q000633:toxicity*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010545:Peroxides / Q000378:metabolism; D011422:Propionates / Q000633:toxicity*; D034741:RNA, Small Interfering / Q000378:metabolism
D007527:Isoenzymes; D009498:Neurotoxins; D009574:Nitro Compounds; D010545:Peroxides; D011422:Propionates; D034741:RNA, Small Interfering; D000255:Adenosine Triphosphate; D003576:Electron Transport Complex IV; C015392:3-nitropropionic acid