Inhibition of mitochondrial complex IV leads to secondary loss complex II-III activity: implications for the pathogenesis and treatment of mitochondrial encephalomyopathies.
Mitochondrial encephalomyopathies, arising from deficiencies of the electron transport chain (ETC) give rise to a wide clinical spectrum of presentation and are often progressive in nature. The aetiology of mitochondrial encephalomyopathies have yet to be fully elucidated, however, a successive loss of ETC function may contribute to the progressive nature of these disorders. The possibility arises that as a consequence of a primary impairment of ETC activity, secondary damage to the ETC may occur. In order to investigate this hypothesis, we established a model of cytochrome oxidase (Complex IV) deficiency in cultured human astrocytoma 1321N cells. Potassium cyanide (KCN, 1mM) resulted in a sustained 50% (p<0.01) loss of complex IV. At 24h activities of the other ETC complexes were unaffected. However, at 72h significant loss of succinate-cytochrome c reductase (complex II-III) activity expressed as a ratio to the mitochondrial marker, citrate synthase was observed. (KCN treated; 0.065+/-0.011 vs controls; 0.118+/-0.017 mean+/-SEM, n=8, p<0.05). These results provide a possible mechanism for the progressive nature of ETC defects and why in some patients multiple patterns of ETC deficiencies can be demonstrated.
Hargreaves
I P
IP
Neurometabolic Unit, National Hospital and Department of Molecular Neuroscience, Institute of Neurology, Queen Square, London WC1N 3BG, UK. ihargrea@ion.ucl.ac.uk
Duncan
A J
AJ
Wu
L
L
Agrawal
A
A
Land
J M
JM
Heales
S J R
SJ
D001254:Astrocytoma / Q000378:metabolism; D002460:Cell Line; D002950:Citrate (si)-Synthase / Q000378:metabolism; D003067:Coenzymes / Q000378:metabolism; D042963:Electron Transport Complex II / Q000378:metabolism*; D014450:Electron Transport Complex III / Q000378:metabolism*; D003576:Electron Transport Complex IV / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D017237:Mitochondrial Encephalomyopathies / Q000201:enzymology* / Q000473:pathology* / Q000628:therapy; D011189:Potassium Chloride / Q000494:pharmacology; D011485:Protein Binding; D014451:Ubiquinone / Q000031:analogs & derivatives / Q000378:metabolism
D003067:Coenzymes; D014451:Ubiquinone; D011189:Potassium Chloride; D042963:Electron Transport Complex II; D003576:Electron Transport Complex IV; D002950:Citrate (si)-Synthase; D014450:Electron Transport Complex III; C024989:coenzyme Q10; D005978:Glutathione