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MitoQ regulates redox-related non-coding RNAs to preserve mitochondrial network integrity in pressure overload heart failure.

07:00 EST 31st January 2020 | BioPortfolio

Summary of "MitoQ regulates redox-related non-coding RNAs to preserve mitochondrial network integrity in pressure overload heart failure."

Evidence suggests that mitochondrial network integrity is impaired in cardiomyocytes from failing hearts. While oxidative stress has been implicated in heart failure (HF)-associated mitochondrial remodeling, the effect of mitochondrial-targeted antioxidants, such as mitoquinone (MitoQ), on the mitochondrial network in a model of heart failure (HF) (e.g. pressure overload) has not been demonstrated. Furthermore, the mechanism of this regulation is not completely understood with an emerging role for post-transcriptional regulation long non-coding RNAs (lncRNA). We hypothesize that MitoQ preserves mitochondrial fusion proteins (i.e. Mfn2) through redox-sensitive lncRNAs, leading to improved mitochondrial network integrity in HF. To test the hypothesis, 8-weeks old C57BL/6J mice were subjected to ascending aortic constriction (AAC), which caused substantial left ventricular (LV) chamber remodeling and contractile dysfunction in one week. Transmission electron microscopy and immunostaining revealed defective inter-mitochondrial and mitochondrial-sarcoplasmic reticulum (SR) ultrastructure in AAC mice compared to Sham-operated animals, which was accompanied by elevated oxidative stress and suppressed MFN2 expression. MitoQ (1.36 mg/day/mouse, 7 consecutive days) significantly ameliorated LV contractile dysfunction, attenuated Mfn2 protein downregulation, improved inter-organellar contact, and increased metabolism-related gene expression. Moreover, our data from both mice and isolated cardiomyocytes revealed that MitoQ alleviated the dysregulation of a -associated lncRNA (i.e. ). In summary, the present study supports a unique mechanism by which MitoQ improves myocardial inter-organellar network in HF by maintaining expression regulation by lncRNAs. These findings underscore the role of lncRNAs in the pathogenesis of HF, and the potential of targeting lncRNAs as novel therapeutic strategy for HF treatment.

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This article was published in the following journal.

Name: American journal of physiology. Heart and circulatory physiology
ISSN: 1522-1539
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Medical and Biotech [MESH] Definitions

Double-stranded DNA of MITOCHONDRIA. In eukaryotes, the mitochondrial GENOME is circular and codes for ribosomal RNAs, transfer RNAs, and about 10 proteins.

Small double-stranded, non-protein coding RNAs, 21-25 nucleotides in length generated from single-stranded microRNA gene transcripts by the same RIBONUCLEASE III, Dicer, that produces small interfering RNAs (RNA, SMALL INTERFERING). They become part of the RNA-INDUCED SILENCING COMPLEX and repress the translation (TRANSLATION, GENETIC) of target RNA by binding to homologous 3'UTR region as an imperfect match. The small temporal RNAs (stRNAs), let-7 and lin-4, from C. elegans, are the first 2 miRNAs discovered, and are from a class of miRNAs involved in developmental timing.

Cytochromes of the c type that are found in eukaryotic MITOCHONDRIA. They serve as redox intermediates that accept electrons from MITOCHONDRIAL ELECTRON TRANSPORT COMPLEX III and transfer them to MITOCHONDRIAL ELECTRON TRANSPORT COMPLEX IV.

A mitochondrial uncoupling protein that is expressed in many tissues and exhibits the greatest expression in SKELETAL MUSCLE. It regulates mitochondrial ATP production and the generation of REACTIVE OXYGEN SPECIES.

Small double-stranded, non-protein coding RNAs (21-31 nucleotides) involved in GENE SILENCING functions, especially RNA INTERFERENCE (RNAi). Endogenously, siRNAs are generated from dsRNAs (RNA, DOUBLE-STRANDED) by the same ribonuclease, Dicer, that generates miRNAs (MICRORNAS). The perfect match of the siRNAs' antisense strand to their target RNAs mediates RNAi by siRNA-guided RNA cleavage. siRNAs fall into different classes including trans-acting siRNA (tasiRNA), repeat-associated RNA (rasiRNA), small-scan RNA (scnRNA), and Piwi protein-interacting RNA (piRNA) and have different specific gene silencing functions.

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