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, 1 mM) resulted in a sustained 50% (p < 0.01) loss of complex IV. At 24 h activities of the other ETC complexes were unaffected. However, at 72 h significant loss of succinate-cytochrome c reductase (complex II-IIII) 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. (c) 2007 Elsevier B.V. and Mitochondria Research Society. All rights reserved.