Importance of the mitochondrial amino acid pool in the sensitivity of erythroid cells to chloramphenicol: role of glycine and serine.
The amino acid pool of mitochondria has been recently implicated in the sensitivity of erythroid cells to chloramphenicol (CAP) [8]. In the present study, we have analyzed the composition of that pool in the sensitive erythroleukemia mitochondria (EM) and compared it with that of the resistant chloroma mitochondria (CM). We have also tested the effect of every major component in each pool on the sensitivity to CAP. The study of endogenous amino acid composition of EM and CM was performed with a JEOL 5AH amino acid analyzer, and the sensitivity to the drug was assayed by determining its interaction with the mitochondrial protein synthesis activity. Analysis of the total endogenous pool showed about 20% more amino acids in CM compared to EM. However, some amino acids were present in significantly higher (e.g. glycine, serine and histidine) or lower (e.g. proline, leucine, arginine, glutamic acid and threonine) quantity within EM. When compensating for each low amino acid in either CM or EM by addition of that particular acid to the incubation medium, only glycine and serine had a significant effect. Thus, the addition of glycine or serine enhanced the sensitivity to CAP from 14 to 49-52% in CM, but were without effect in EM. Addition of the other acids to either mitochondria gave little or no effect. Since serine could be interconvertible intramitochondrially to glycine, and because the latter with succinate are the first reactants in heme biosynthesis which is initiated inside the mitochondria, it would appear that erythroid cell sensitivity to CAP is predetermined by the mitochondrial glycine-serine pool and might be somehow related to the pathway of heme biosynthesis in these cells.
D000596:Amino Acids / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D002701:Chloramphenicol / Q000494:pharmacology*; D004912:Erythrocytes / Q000378:metabolism*; D005260:Female; D005998:Glycine / Q000502:physiology*; D066298:In Vitro Techniques; D004915:Leukemia, Erythroblastic, Acute / Q000378:metabolism; D007951:Leukemia, Myeloid / Q000378:metabolism; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D008928:Mitochondria / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000096:biosynthesis; D051381:Rats; D012694:Serine / Q000502:physiology*
D000596:Amino Acids; D009363:Neoplasm Proteins; D012694:Serine; D002701:Chloramphenicol; D005998:Glycine