Metabolic balancing by miR-276 shapes the mosquito reproductive cycle and  Plasmodium falciparum  development

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Abstract

The blood-feeding behavior of Anopheles females delivers essential nutrients for egg development and drives parasite transmission between humans. Plasmodium growth is adapted to the vector reproductive cycle, but how changes in the reproductive cycle impact parasite development remains unclear. Here, we show that the bloodmeal-induced miR-276-5p fine-tunes the expression of branched-chain amino acid transferase to terminate the reproductive cycle. Silencing of miR-276 prolongs high rates of amino acid (AA) catabolism and increases female fertility, suggesting that timely termination of AA catabolism restricts mosquito investment into reproduction. Prolongation of AA catabolism in P. falciparum-infected females also compromises the development of the transmissible sporozoite forms. Our results suggest that Plasmodium sporogony exploits the surplus mosquito resources available after reproductive investment and demonstrate the crucial role of the mosquito AA metabolism in within-vector parasite proliferation and malaria transmission.

Abstract

Plasmodium growth is adapted to the reproductive cycle of mosquitoes, but underlying mechanisms are unclear. Here, Lampe et al. show that the blood-meal induced miR-276 balances the termination of the mosquito amino acid catabolism and egg development, providing nutrients for Plasmodium sporozoite development.

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Defective Branched-Chain Amino Acid Catabolism Disrupts Glucose Metabolism and Sensitizes the Heart to Ischemia-Reperfusion Injury.

Tao Li, Zhen Zhang, Stephen Kolwicz … (2017)

Elevated levels of branched-chain amino acids (BCAAs) have recently been implicated in the development of cardiovascular and metabolic diseases, but the molecular mechanisms are unknown. In a mouse model of impaired BCAA catabolism (knockout [KO]), we found that chronic accumulation of BCAAs suppressed glucose metabolism and sensitized the heart to ischemic injury. High levels of BCAAs selectively disrupted mitochondrial pyruvate utilization through inhibition of pyruvate dehydrogenase complex (PDH) activity. Furthermore, downregulation of the hexosamine biosynthetic pathway in KO hearts decreased protein O-linked N-acetylglucosamine (O-GlcNAc) modification and inactivated PDH, resulting in significant decreases in glucose oxidation. Although the metabolic remodeling in KO did not affect baseline cardiac energetics or function, it rendered the heart vulnerable to ischemia-reperfusion injury. Promoting BCAA catabolism or normalizing glucose utilization by overexpressing GLUT1 in the KO heart rescued the metabolic and functional outcome. These observations revealed a novel role of BCAA catabolism in regulating cardiac metabolism and stress response.

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Disruption of BCATm in mice leads to increased energy expenditure associated with the activation of a futile protein turnover cycle.

Kate S. Hutson, Andras Hajnal, Sean Lynch … (2007)

Leucine is recognized as a nutrient signal; however, the long-term in vivo consequences of leucine signaling and the role of branched-chain amino acid (BCAA) metabolism in this signaling remain unclear. To investigate these questions, we disrupted the BCATm gene, which encodes the enzyme catalyzing the first step in peripheral BCAA metabolism. BCATm(-/-) mice exhibited elevated plasma BCAAs and decreased adiposity and body weight, despite eating more food, along with increased energy expenditure, remarkable improvements in glucose and insulin tolerance, and protection from diet-induced obesity. The increased energy expenditure did not seem to be due to altered locomotor activity, uncoupling proteins, sympathetic activity, or thyroid hormones but was strongly associated with food consumption and an active futile cycle of increased protein degradation and synthesis. These observations suggest that elevated BCAAs and/or loss of BCAA catabolism in peripheral tissues play an important role in regulating insulin sensitivity and energy expenditure.

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TargetSearch - a Bioconductor package for the efficient preprocessing of GC-MS metabolite profiling data

Alvaro Cuadros-Inostroza, Camila Caldana, Henning Redestig … (2009)

Background Metabolite profiling, the simultaneous quantification of multiple metabolites in an experiment, is becoming increasingly popular, particularly with the rise of systems-level biology. The workhorse in this field is gas-chromatography hyphenated with mass spectrometry (GC-MS). The high-throughput of this technology coupled with a demand for large experiments has led to data pre-processing, i.e. the quantification of metabolites across samples, becoming a major bottleneck. Existing software has several limitations, including restricted maximum sample size, systematic errors and low flexibility. However, the biggest limitation is that the resulting data usually require extensive hand-curation, which is subjective and can typically take several days to weeks. Results We introduce the TargetSearch package, an open source tool which is a flexible and accurate method for pre-processing even very large numbers of GC-MS samples within hours. We developed a novel strategy to iteratively correct and update retention time indices for searching and identifying metabolites. The package is written in the R programming language with computationally intensive functions written in C for speed and performance. The package includes a graphical user interface to allow easy use by those unfamiliar with R. Conclusions TargetSearch allows fast and accurate data pre-processing for GC-MS experiments and overcomes the sample number limitations and manual curation requirements of existing software. We validate our method by carrying out an analysis against both a set of known chemical standard mixtures and of a biological experiment. In addition we demonstrate its capabilities and speed by comparing it with other GC-MS pre-processing tools. We believe this package will greatly ease current bottlenecks and facilitate the analysis of metabolic profiling data.

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Author and article information

Contributors

Elena A. Levashina:

ORCID: http://orcid.org/0000-0003-4605-906X

levashina@mpiib-berlin.mpg.de

Journal

Journal ID (nlm-ta): Nat Commun

Journal ID (iso-abbrev): Nat Commun

Title: Nature Communications

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2041-1723

Publication date (Electronic): 10 December 2019

Publication date PMC-release: 10 December 2019

Publication date Collection: 2019

Volume: 10

Electronic Location Identifier: 5634

Affiliations

[1 ]ISNI 0000 0004 0491 2699, GRID grid.418159.0, Vector Biology Unit, Max Planck Institute for Infection Biology, ; Charitéplatz 1, 10117 Berlin, Germany

[2 ]metaSysX GmbH, 14476 Potsdam-Golm, Germany

[3 ]ISNI 0000 0004 1795 1830, GRID grid.451388.3, Present Address: Physiology and Metabolism Laboratory, , Francis Crick Institute, ; 1 Midland Road, NW1 1AT London, UK

Author information

Elena A. Levashina http://orcid.org/0000-0003-4605-906X

Article

Publisher ID: 13627

DOI: 10.1038/s41467-019-13627-y

PMC ID: 6904670

PubMed ID: 31822677

SO-VID: cc34c292-a088-4244-8f5a-a1f5b3cb3bdd

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 25 February 2019

Date accepted : 14 November 2019

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ScienceOpen disciplines: Uncategorized

Keywords: metabolomics,parasite development,mirnas,malaria

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ScienceOpen disciplines: Uncategorized

Keywords: metabolomics, parasite development, mirnas, malaria

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Metabolic balancing by miR-276 shapes the mosquito reproductive cycle and Plasmodium falciparum development

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Defective Branched-Chain Amino Acid Catabolism Disrupts Glucose Metabolism and Sensitizes the Heart to Ischemia-Reperfusion Injury.

Disruption of BCATm in mice leads to increased energy expenditure associated with the activation of a futile protein turnover cycle.

TargetSearch - a Bioconductor package for the efficient preprocessing of GC-MS metabolite profiling data

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Cited by 17

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