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Loss of UCP2 attenuates mitochondrial dysfunction without altering ROS production and uncoupling activity.

ABSTRACT: Although mitochondrial dysfunction is often accompanied by excessive reactive oxygen species (ROS) production, we previously showed that an increase in random somatic mtDNA mutations does not result in increased oxidative stress. Normal levels of ROS and oxidative stress could also be a result of an active compensatory mechanism such as a mild increase in proton leak. Uncoupling protein 2 (UCP2) was proposed to play such a role in many physiological situations. However, we show that upregulation of UCP2 in mtDNA mutator mice is not associated with altered proton leak kinetics or ROS production, challenging the current view on the role of UCP2 in energy metabolism. Instead, our results argue that high UCP2 levels allow better utilization of fatty acid oxidation resulting in a beneficial effect on mitochondrial function in heart, postponing systemic lactic acidosis and resulting in longer lifespan in these mice. This study proposes a novel mechanism for an adaptive response to mitochondrial cardiomyopathy that links changes in metabolism to amelioration of respiratory chain deficiency and longer lifespan.

SUBMITTER: Kukat A

PROVIDER: S-EPMC4063685 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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Loss of UCP2 attenuates mitochondrial dysfunction without altering ROS production and uncoupling activity.

Kukat Alexandra A Dogan Sukru Anil SA Edgar Daniel D Mourier Arnaud A Jacoby Christoph C Maiti Priyanka P Mauer Jan J Becker Christina C Senft Katharina K Wibom Rolf R Kudin Alexei P AP Hultenby Kjell K Flögel Ulrich U Rosenkranz Stephan S Ricquier Daniel D Kunz Wolfram S WS Trifunovic Aleksandra A

PLoS genetics 20140619 6

Although mitochondrial dysfunction is often accompanied by excessive reactive oxygen species (ROS) production, we previously showed that an increase in random somatic mtDNA mutations does not result in increased oxidative stress. Normal levels of ROS and oxidative stress could also be a result of an active compensatory mechanism such as a mild increase in proton leak. Uncoupling protein 2 (UCP2) was proposed to play such a role in many physiological situations. However, we show that upregulation ...[more]

PMID: 24945157

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Project description:Purpose:RNA-Seq analysis was performed on mouse hearts with or without hispidulin treatment 4 weeks after arotic banding or sham surgery to determining the effect of hispidulin on pressure overload induced cardiac hypertrophy. Methods: the mRNA profiles of mouse hearts underwent sham or arotic banding surgery with treatment of hispidulin or DMSO were generated by RNA-seq analysis in triplicate. The expression level of gene was calculated by RSEM(v.1.2.12). Differential expression analysis was performed using the DESeq2(V 1.4.5). Results: RNA isolation, library construction, and sequencing were performed on a BGISEQ-500 (Beijing Genomic Institution, www.genomics.org.cn, BGI). For the gene expression analysis, the fold changes were also estimated according to the fragments per kilobase of exon per million fragments mapped (FPKM) in each sample. The significance of different gene expression was defined by the following filter criteria: false discovery rate (FDR) ≤0.001 and log2-ratio 1. After comparing of DMSO+AB group and hispidulin+AB group, we found that 113 genes were significantly differentially expressed. Gene ontology and cluster analysis indicated that alternated genes were enriched in fatty acid oxidation, glucose metabolism, TCA cycle, oxidative phosphorylation, hypertrophic cardiomyopathy, ECM organism, oxidative stress and unfolded protein binding. This result indicated that hispidulin improved mitochondrial function. Conclusions: Our study represents the first detailed analysis of heart transcriptomes, with biologic replicates, generated by RNA-seq technology. The optimized data analysis workflows reported here should provide a framework for comparative investigations of expression profiles. Our results show that NGS offers a comprehensive and more accurate quantitative and qualitative evaluation of mRNA content within a cell or tissue. We conclude that RNA-seq based transcriptome characterization would expedite genetic network analyses and permit the dissection of complex biologic functions.

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Loss of UCP2 attenuates mitochondrial dysfunction without altering ROS production and uncoupling activity.

Publications

Loss of UCP2 attenuates mitochondrial dysfunction without altering ROS production and uncoupling activity.

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