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The Journal of Neuroscience, November 19, 2008, 28(47):12581-12590; doi:10.1523/JNEUROSCI.3338-08.2008

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 Previous Article

Cellular/Molecular
MicroRNA-338 Regulates Local Cytochrome c Oxidase IV mRNA Levels and Oxidative Phosphorylation in the Axons of Sympathetic Neurons

Armaz Aschrafi, Azik D. Schwechter, Marie G. Mameza, Orlangie Natera-Naranjo, Anthony E. Gioio, and Barry B. Kaplan

Laboratory of Molecular Biology, National Institute of Mental Health–National Institutes of Health, Bethesda, Maryland 20892-1381

Correspondence should be addressed to Dr. Barry B. Kaplan, Molecular Neurobiology Section, Laboratory of Molecular Biology, National Institute of Mental Health, Building 10, Room 4A15, 10 Center Drive, Bethesda, MD 20892-1381. Email: kaplanb{at}mail.nih.gov

MicroRNAs (miRs) are evolutionarily conserved, noncoding RNA molecules of 21 nt that regulate the expression of genes that are involved in various biological processes, such as cell proliferation and differentiation. Previously, we reported the presence of a heterogeneous population of mRNAs present in the axons and nerve terminals of primary sympathetic neurons to include the nuclear-encoded mitochondrial mRNA coding for COXIV. Sequence analysis of the 3'UTR of this mRNA revealed the presence of a putative binding site for miR-338, a brain-specific microRNA. Transfection of precursor miR-338 into the axons of primary sympathetic neurons decreases COXIV mRNA and protein levels and results in a decrease in mitochondrial activity, as measured by the reduction of ATP levels. Conversely, the transfection of synthetic anti-miR oligonucleotides that inhibit miR-338 increases COXIV levels, and results in a significant increase in oxidative phosphorylation and also norepinephrine uptake in the axons. Our results point to a molecular mechanism by which this microRNA participates in the regulation of axonal respiration and function by modulating the levels of COXIV, a protein which plays a key role in the assembly of the mitochondrial cytochrome c oxidase complex IV.

Key words: mitochondria; ATP synthesis; RNA localization; inhibitory RNA; oxidative phosphorylation; local translation; norepinephrine uptake

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Received July 16, 2008; revised Aug. 11, 2008; accepted Oct. 15, 2008.

Correspondence should be addressed to Dr. Barry B. Kaplan, Molecular Neurobiology Section, Laboratory of Molecular Biology, National Institute of Mental Health, Building 10, Room 4A15, 10 Center Drive, Bethesda, MD 20892-1381. Email: kaplanb{at}mail.nih.gov

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