MicroRNA-338 regulates local cytochrome c oxidase IV mRNA levels and oxidative phosphorylation in the axons of sympathetic neurons.
MicroRNAs (miRs) are evolutionarily conserved, noncoding RNA molecules of approximately 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.
Aschrafi
Armaz
A
Laboratory of Molecular Biology, National Institute of Mental Health-National Institutes of Health, Bethesda, Maryland 20892-1381, USA.
Schwechter
Azik D
AD
Mameza
Marie G
MG
Natera-Naranjo
Orlangie
O
Gioio
Anthony E
AE
Kaplan
Barry B
BB
D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D000906:Antibodies / Q000494:pharmacology; D001369:Axons / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D002478:Cells, Cultured; D003576:Electron Transport Complex IV / Q000235:genetics* / Q000378:metabolism; D039642:Eukaryotic Initiation Factors / Q000378:metabolism; D035683:MicroRNAs / Q000276:immunology / Q000378:metabolism*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000166:cytology* / Q000378:metabolism*; D018377:Neurotransmitter Agents / Q000378:metabolism; D010085:Oxidative Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D017783:Superior Cervical Ganglion / Q000166:cytology*; D014162:Transfection / Q000379:methods; D014316:Tritium / Q000378:metabolism
D000906:Antibodies; D039642:Eukaryotic Initiation Factors; D035683:MicroRNAs; D018377:Neurotransmitter Agents; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D014316:Tritium; D003576:Electron Transport Complex IV