Hepatic cobalamin deficiency induced by hydroxycobalamin[c-lactam] treatment in rats is associated with decreased mitochondrial mRNA contents and accumulation of polycistronic mitochondrial RNAs.
Treatment of rats with hydroxycobalamin[c-lactam] (HCCL), a cobalamin antagonist, results in both increased hepatic mitochondrial content and the development of defects in mitochondrial ubiquinol:cytochrome c oxidoreductase and cytochrome c oxidase. The present study was designed to evaluate changes in hepatic mitochondrial RNA contents in response to HCCL treatment in rats. After 2 weeks of HCCL treatment, hepatic contents of the mature mitochondrial mRNAs (expressed normalized to 28 S rRNA) encoding subunit II of cytochrome c oxidase (CO II), subunit 1 of NADH dehydrogenase (ND1), and cytochrome b were reduced to values 40-60% of those observed in RNA from control liver tissue. In addition, HCCL induced a pronounced accumulation of high molecular weight RNA species which hybridized to mitochondrial probes and represented polycistronic RNA sequences. The polycistronic RNAs were products of the heavy strand of the mitochondrial genome, and major species demonstrated hybridization patterns consistent with identifications corresponding to the 12-16 S rRNA, 12-16 S-ND1, 16 S-ND1, and CO II-ATP synthase subunit 6 regions of the mitochondrial genome. Maximal expression of the polycistronic mitochondrial RNA was observed after 2 weeks of HCCL treatment. Thus, HCCL treatment interferes with mitochondrial RNA processing and decreases the content of mature mitochondrial mRNAs. Altered expression of the mitochondrial genome may be responsible for the decreased electron transport chain activity known to result from HCCL administration.
Leeds
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Department of Medicine, Case Western Reserve University, Cleveland, Ohio 44106-4981.
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D000818:Animals; D003576:Electron Transport Complex IV / Q000235:genetics; D005796:Genes; D008297:Male; D008930:Mitochondria, Liver / Q000378:metabolism*; D008970:Molecular Weight; D009245:NADH Dehydrogenase / Q000235:genetics; D012313:RNA / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D000077278:RNA, Mitochondrial; D012336:RNA, Ribosomal, 16S / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014805:Vitamin B 12 / Q000031:analogs & derivatives* / Q000494:pharmacology; D014806:Vitamin B 12 Deficiency / Q000378:metabolism*
D012333:RNA, Messenger; D000077278:RNA, Mitochondrial; D012336:RNA, Ribosomal, 16S; C071541:hydroxycobalamin(c-lactam); D012313:RNA; D009245:NADH Dehydrogenase; D003576:Electron Transport Complex IV; D014805:Vitamin B 12