Perturbation by clofibrate of mitochondrial levels in animal cells. Implications for a model of mitochondrial genesis.
Dietary treatment of rats for 2 weeks with clofibrate (ethyl 2-(4-chlorophenoxy)-2-methylproprionate), a hypolipidemic drug, increased the ratio of mitochondrial protein to cellular DNA by 2-fold, yet the recovery, purity, and structural integrity of mitochondria from treated livers were identical with the controls. Apparent half-lives of total protein in control and treated mitochondria were measured using [14C]bicarbonate as an amino acid precursor and were found to be the same. In a double label study, the relative half-lives of total mitochondrial proteins or mitochondrial inner membrane, matrix, or outer compartment proteins were compared in control and treated livers. In no case did drug treatment alter the apparent rates of degradation of protein. Coulter counting of the mitochondrial fraction revealed a 2-fold increase in counts relative to cellular DNA but counts per mg of mitochondrial protein were the same as control. Cytochrome spectra of mitochondria or purified inner membranes were not qualitatively different in control versus treated preparations. Sodium dodecyl sulfate gel electrophoretic patterns of mitochondria or submitochondrial fractions were very similar for control and treated livers. Inner compartment marker enzymes were unchanged in specific activity, but monoamine oxidase, an outer compartment marker, was decreased in specific activity. Clofibrate treatment appears to result in an increased synthesis of the majority of mitochondrial protein. The effects of clofibrate are consistent with a model of mitochondrial turnover in which the control of outer compartment synthesis and degradation is different from that of the inner compartment. A model is proposed for mitochondrial genesis and degradation in normal and clofibrate-treated livers.
D000818:Animals; D002994:Clofibrate / Q000494:pharmacology*; D003580:Cytochromes / Q000378:metabolism; D004261:DNA Replication / Q000187:drug effects*; D004272:DNA, Mitochondrial / Q000235:genetics*; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008854:Microscopy, Electron; D008930:Mitochondria, Liver / Q000378:metabolism* / Q000648:ultrastructure; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D013053:Spectrophotometry
D003580:Cytochromes; D004272:DNA, Mitochondrial; D002994:Clofibrate