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–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.