J. Biol. Chem., Vol. 269, Issue 6, 3947-3951, Feb, 1994
Hepatic cobalamin deficiency induced by hydroxycobalamin[c-lactam] treatment in rats is associated with decreased mitochondrial mRNA contents and accumulation of polycistronic mitochondrial RNAs
FS Leeds and EP Brass
Department of Medicine, Case Western Reserve University, Cleveland, Ohio 44106-4981.
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.
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