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

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

doi:10.1007/s00018-012-1064-8

Cited by 88 publications

(92 citation statements)

References 51 publications

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“…6C). Importantly, reporter transcripts containing the SV40 3 ′ UTR have been shown to be restricted to the cell bodies of primary neurons, and have previously been used as negative controls in studies of axonal localization of mRNAs (Goetze et al 2003;Aschrafi et al 2012).…”

Section: Local Synthesis Of Th Facilitates Axonal Dopamine Productionmentioning

confidence: 99%

The local expression and trafficking of tyrosine hydroxylase mRNA in the axons of sympathetic neurons

Gervasi

Scott

Aschrafi

et al. 2016

RNA

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Synthesis and regulation of catecholamine neurotransmitters in the central nervous system are implicated in the pathogenesis of a number of neuropsychiatric disorders. To identify factors that regulate the presynaptic synthesis of catecholamines, we tested the hypothesis that the rate-limiting enzyme of the catecholamine biosynthetic pathway, tyrosine hydroxylase (TH), is locally synthesized in axons and presynaptic nerve terminals of noradrenergic neurons. To isolate pure axonal mRNA and protein, rat superior cervical ganglion sympathetic neurons were cultured in compartmentalized Campenot chambers. qRT-PCR and RNA in situ hybridization analyses showed that TH mRNA is present in distal axons. Colocalization experiments with nerve terminal marker proteins suggested that both TH mRNA and protein localize in regions of the axon that resemble nerve terminals (i.e., synaptic boutons). Analysis of polysome-bound RNA showed that TH mRNA is present in polysomes isolated from distal axons. Metabolic labeling of axonally synthesized proteins labeled with the methionine analog, L-azidohomoalanine, showed that TH is locally synthesized in axons. Moreover, the local transfection and translation of exogenous TH mRNA into distal axons facilitated axonal dopamine synthesis. Finally, using chimeric td-Tomato-tagged constructs, we identified a sequence element within the TH 3 ′ UTR that is required for the axonal localization of the reporter mRNA. Taken together, our results provide the first direct evidence that TH mRNA is trafficked to the axon and that the mRNA is locally translated. These findings raise the interesting possibility that the biosynthesis of the catecholamine neurotransmitters is locally regulated in the axon and/or presynaptic nerve terminal.

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Section: Local Synthesis Of Th Facilitates Axonal Dopamine Productionmentioning

confidence: 99%

The local expression and trafficking of tyrosine hydroxylase mRNA in the axons of sympathetic neurons

Gervasi

Scott

Aschrafi

et al. 2016

RNA

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“…MiR-338-3p is implicated in the influence of mitochondrial function in neurons, specifically altering axonal expression of cytochrome c oxidase IV and ATP5G1 expression. 39, 40 Its precise role in myocardial tissue remains to be resolved. It has been suggested that several anesthetic agents including isoflurane, 41 opioids, 42 and propofol 43 have preconditioning effects that may interfere with RIPC.…”

Section: Circulation Research February 28 2014mentioning

confidence: 99%

Remote Ischemic Preconditioning Preserves Mitochondrial Function and Influences Myocardial MicroRNA Expression in Atrial Myocardium During Coronary Bypass Surgery

Slagsvold

Rognmo

Høydal

et al. 2014

Circulation Research

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Rationale: Remote ischemic preconditioning (RIPC) has been suggested to induce cardioprotection during cardiac surgery. Maintaining proper atrial function is imperative in preventing arrhythmia and thrombus formation. Mitochondria have been proposed as key targets in conveying RIPC mechanisms and effects. MicroRNA (miR) is emerging as an important regulator of mitochondrial function, arrhythmia, and protection from ischemia and reperfusion. Objective: This study aimed to evaluate the effect of RIPC on mitochondrial respiration and miR expression in human atrial tissue. Methods and Results: Sixty patients undergoing coronary artery bypass graft surgery were randomized to RIPC (n=30) or control (n=30). RIPC was performed preoperatively by inflating a blood pressure cuff on the upper arm to 200 mm Hg for 3×5 minutes, with 5 minutes reperfusion intervals. Biopsies were obtained from the right atrial appendage before and after aortic cross-clamping. Mitochondrial respiration was measured in situ and miR assessed by commercial miR array and quantitative reverse transcription polymerase chain reaction. Postoperative atrial fibrillation occurrence was monitored by biotelemetry. Maximal mitochondrial respiration was preserved throughout surgery after RIPC but significantly reduced (−28%; P <0.05) after aortic cross-clamping in control. Incidence of postoperative atrial fibrillation was lower after RIPC versus control (14% versus 50%; P <0.01). Myocardial expression of miR-133a and miR-133b increased after aortic cross-clamping in both RIPC and control, whereas miR-1 was upregulated in control only. MiR-338-3p expression was higher in RIPC versus control after aortic cross-clamping. Conclusions: RIPC preserves mitochondrial respiration and prevents upregulation of miR-1 in the right atrium during coronary artery bypass graft. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT01308138

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“…The potential influence of subunit-specific degradation rates on COX transcript profiles has not been well studied, and not in the context of thermal acclimation in an ectothermic animal. To date in mammals there is some evidence for a role of mRNA degradation in the control of COX4 (Zhang and Wong-Riley, 2000), and a role for miRNA in the control of nuclear-encoded COX genes [miRNA-338 (Aschrafi et al, 2012)], mitochondrial-encoded COX genes [miRNA-181c (Das et al, 2012)] and COX assembly [miRNA-210 (Colleoni et al, 2013)]. …”

Section: Research Articlementioning

confidence: 99%

“…In some scenarios, mRNA can be stalled in translation and accumulate in socalled stress granules or P-bodies, also known as RNA interference (Balagopal and Parker, 2009). The role for miRNA in the control of nuclear-encoded COX genes (Aschrafi et al, 2012), COX assembly (Colleoni et al, 2013) and mitochondrial-encoded COX mRNA (Das et al, 2012) has not been evaluated in the context of thermal remodelling of mitochondrial metabolism. This process of gene silencing would allow an mRNA species to accumulate, and re-enter translation when needed.…”

Section: Research Articlementioning

confidence: 99%

mRNA degradation: an underestimated factor on steady-state transcript levels of cytochromecoxidase subunits?

Bremer

Moyes

2014

Journal of Experimental Biology

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Steady-state mRNA levels are determined by synthesis and degradation; however, changes in mRNA levels are usually attributed to transcription. For cytochrome c oxidase (COX), cold acclimation typically leads to an increase in COX activity while transcript levels for the nuclear-encoded subunits change non-stoichiometrically. Whether those patterns are caused by differences in subunit transcription rates, decay rates or both was not known. We assessed decay rates of transcripts for COX subunits, including representatives that decreased, increased in parallel with COX or increased in excess of COX. Low temperature reduced the decay rate of all transcripts; however, COX subunits displayed higher thermal sensitivity than housekeeping genes. The lower decay rates for COX transcripts might explain some of their increase in response to cold acclimation. The reason for the exaggerated transcript response of two subunits (COX6B-1 and COX7A-2) may be due to decreased decay. However, decay rate differences could not explain the patterns seen with another subunit that did not change in mRNA level with thermal acclimation (COX6A-2). Further, the decay patterns differed between two thermal acclimation experiments, which may explain some of the heterogeneity seen in fish studies. The differences in decay rates suggest that the lack of stoichiometry in mRNA levels is exacerbated by post-transcriptional mechanisms. Collectively, these results suggest that temperature-induced differences in COX subunit mRNA levels and deviations from stoichiometry between them may partially arise from subunit-specific sensitivities to degradation. We suggest that all subunits are controlled by transcription, and that exaggerated responses of some subunits are due to reduced decay rates.

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

Cited by 88 publications

References 51 publications

The local expression and trafficking of tyrosine hydroxylase mRNA in the axons of sympathetic neurons

The local expression and trafficking of tyrosine hydroxylase mRNA in the axons of sympathetic neurons

Remote Ischemic Preconditioning Preserves Mitochondrial Function and Influences Myocardial MicroRNA Expression in Atrial Myocardium During Coronary Bypass Surgery

mRNA degradation: an underestimated factor on steady-state transcript levels of cytochromecoxidase subunits?

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