The effect of long-term inhibition of mitochondrial protein synthesis on the oxidation capacity of mitochondria for NADH-linked substrates

Experiments are presented showing that specific inhibition of mitochondrial protein synthesis by tetracyclines decreases the activity of the NADH-dehydrogenase complex in liver mitochondria, if rats are treated for long periods with these antibiotics. The corresponding inhibition of this complex in tumor cells (Zajdela hepatoma) and tumor mitochondria (Leydig cell tumor) is even more pronounced. It is concluded that the mitochondrial genetic system is involved in the assembly of the NADH-dehydrogenase complex, most likely by coding for one or more subunits. It is argued that this information, contrary to the situation for cytochrome oxidase, the cytochrome bc1 complex and ATPsynthase, has been missed in previous experiments employing differential inhibition of mitochondrial protein synthesis, because of the circumstance that the inhibition did not reach the level at which it became rate-limiting

The mitochondrial genetic system as a target for chemotherapy:Tetracyclines as cytostatics

The mitochondrial genetic system is indispensable for the biosynthesis of the enzyme complexes involved in aerobic energy generation. Tetracyclines inhibit the expression of only the mitochondrial genes because they specifically block mitochondrial protein synthesis. A salient feature is that this inhibition occurs at the low concentration required for anti-bacterial treatment, provided that this concentration is maintained continuously. Evidence is presented that the growth of carcinogen-induced tumors can be inhibited by tetracyclines. It is further shown that the development in the cheek pouch of the Syrian hamster of a transplantable hypernephroma from human origin can be strongly retarded by tetracyclines as well. Therefore, the mitochondrial genetic system has to be reckoned as a target for chemotherapy and tetracyclines as cytostatic agents

Different effects of oxytetracycline and doxycycline on mitochondrial protein synthesis in rat liver after long-term treatment

The tetracyclines inhibit specifically mitochondrial (mt) and bacterial protein synthesis when they are present in low concentrations (2–10 μg/ml). There is no difference between the various members of this group of antibiotics in this respect. In the present study, however, it is shown that the inhibitory effect of doxycycline on mt-protein synthesis in rat liver is partially lost after continuous treatment for more than 1 week, whereas oxytetracycline continues to inhibit mt-protein synthesis effectively after 1 week of treatment. To find an explanation for this difference between doxycycline and oxytetracycline, a detailed study was made of the distribution and the effects on mt-protein synthesis of both tetracyclines under various conditions in rat liver. The results of the studies lead to the hypothesis that doxycycline treatment induces the formation of a doxycycline complex, and thus to a reduced amount of free doxycycline. This may explain the loss of effective inhibition of mt-protein synthesi