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MicroRNA-338 regulates the axonal expression of multiple nuclear-encoded mitochondrial mRNAs encoding subunits of the oxidative phosphorylation machinery

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Abstract

MicroRNAs (miRNAs) constitute a novel class of small, non-coding RNAs that act as post-transcriptional regulators of gene expression. Remarkably, it has been shown that these small molecules can coordinately regulate multiple genes coding for proteins with related cellular functions. Previously, we reported that brain-specific miR-338 modulates the axonal expression of cytochrome c oxidase IV (COXIV), a nuclear-encoded mitochondrial protein that plays a key role in oxidative phosphorylation and axonal function. Here, we report that ATP synthase (ATP5G1), like COXIV mRNA, contains a putative miR-338 binding site, and that modulation of miR-338 levels in the axon results in alterations in both COXIV and ATP5G1 expression. Importantly, miR-338 modulation of local COXIV and ATP5G1 expression has a marked effect on axonal ROS levels, as well as axonal growth. These findings point to a mechanism by which miR-338 modulates local energy metabolism through the coordinate regulation of the expression of multiple nuclear-encoded mitochondrial mRNAs in the axon.

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Abbreviations

H2DCFDA:

5-(and-6)-Carboxy-2′, 7′-dichlorodihydrofluorescein diacetate

NDGA:

Nordihydraguaiaretic acid

COX:

Cytochorome oxidase

qRT-PCR:

Quantitative real-time reverse transcriptase polymerase chain reaction

miRNA:

MicroRNA

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Acknowledgments

This work was supported by the Division of Intramural Research Programs of the National Institute of Mental Health. We thank Ms. Sanah Vohra for her invaluable technical assistance.

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Authors and Affiliations

  1. Laboratory of Molecular Biology, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, 20892-1381, USA

    Armaz Aschrafi, Amar N. Kar, Orlangie Natera-Naranjo, Margaret A. MacGibeny, Anthony E. Gioio & Barry B. Kaplan

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  1. Armaz Aschrafi
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Correspondence to Barry B. Kaplan.

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Aschrafi, A., Kar, A.N., Natera-Naranjo, O. et al. MicroRNA-338 regulates the axonal expression of multiple nuclear-encoded mitochondrial mRNAs encoding subunits of the oxidative phosphorylation machinery. Cell. Mol. Life Sci. 69, 4017–4027 (2012). https://doi.org/10.1007/s00018-012-1064-8

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  • DOI: https://doi.org/10.1007/s00018-012-1064-8

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