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Mitochondrial reactive oxygen species modulate mosquito susceptibility to Plasmodium infection.

Gonçalves RL, Oliveira JH, Oliveira GA, Andersen JF, Oliveira MF, Oliveira PL, Barillas-Mury C - PLoS ONE (2012)

Bottom Line: Mitochondria perform multiple roles in cell biology, acting as the site of aerobic energy-transducing pathways and as an important source of reactive oxygen species (ROS) that modulate redox metabolism.AgMC1 silencing reduces mitochondrial membrane potential, resulting in increased proton-leak and uncoupling of oxidative phosphorylation.These metabolic changes reduce midgut ROS generation and increase A. gambiae susceptibility to Plasmodium infection.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, United States of America.

ABSTRACT

Background: Mitochondria perform multiple roles in cell biology, acting as the site of aerobic energy-transducing pathways and as an important source of reactive oxygen species (ROS) that modulate redox metabolism.

Methodology/principal findings: We demonstrate that a novel member of the mitochondrial transporter protein family, Anopheles gambiae mitochondrial carrier 1 (AgMC1), is required to maintain mitochondrial membrane potential in mosquito midgut cells and modulates epithelial responses to Plasmodium infection. AgMC1 silencing reduces mitochondrial membrane potential, resulting in increased proton-leak and uncoupling of oxidative phosphorylation. These metabolic changes reduce midgut ROS generation and increase A. gambiae susceptibility to Plasmodium infection.

Conclusion: We provide direct experimental evidence indicating that ROS derived from mitochondria can modulate mosquito epithelial responses to Plasmodium infection.

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Related in: MedlinePlus

Anopheles gambiae mitochondrial carrier 1 (AgMC1) phylogeny and predicted structure.(A) Phylogenetic tree based on the sequence alignment of the deduced amino acid sequence of AgMC1 (AGAP001297-PA) and the putative mitochondrial carriers from A. aegypti (AaMC1), D. melanogaster (DmMC1), human mitochondrial carriers HsSLC25A-39 and SLC25A-40 and yeast manganese trafficking factor for mitochondrial (ScMTM1); uncoupling proteins from humans (HsUCP), A. gambiae (AgUCP), A. aegypti (AaUCP) and D. melanogaster (DmUCP); putative adenine nucleotide translocators (ANT) from humans (HsANT, SLC25A6), yeast (ScANT), A. gambiae (AgANT) A. aegypti (AaANT), and D. melanogaster (DmANT); putative phosphate carriers (PiC) from humans (HsPiC, SLC25A3), yeast (ScPiC), A. gambiae (AgPiC), A. aegypti (AaPiC,) and D. melanogaster (DmPiC). Sequence alignments and accession numbers are included in Fig. S1. (B) Schematic representation of the AgMC1 protein sequence coding for three mitochondrial carrier domains (mito carr, top panel) highlighted in blue, green and red, and of the predicted secondary structure (bottom panel), consisting of six transmembrane domains (H1 to H6), three matrix domains, (M1 to M3), and cytosolic domains. (E) Predicted tertiary structure based on the amino acid sequence of the AgMC1 based on the known structure of bovine ADP/ATP adenine nucleotide translocator. Ribbon diagram of the predicted structure of AgMC1 from a lateral view (left), or viewed from either the matrix (top right) or intermembrane space side of the mitochondrial membrane (bottom right).
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pone-0041083-g001: Anopheles gambiae mitochondrial carrier 1 (AgMC1) phylogeny and predicted structure.(A) Phylogenetic tree based on the sequence alignment of the deduced amino acid sequence of AgMC1 (AGAP001297-PA) and the putative mitochondrial carriers from A. aegypti (AaMC1), D. melanogaster (DmMC1), human mitochondrial carriers HsSLC25A-39 and SLC25A-40 and yeast manganese trafficking factor for mitochondrial (ScMTM1); uncoupling proteins from humans (HsUCP), A. gambiae (AgUCP), A. aegypti (AaUCP) and D. melanogaster (DmUCP); putative adenine nucleotide translocators (ANT) from humans (HsANT, SLC25A6), yeast (ScANT), A. gambiae (AgANT) A. aegypti (AaANT), and D. melanogaster (DmANT); putative phosphate carriers (PiC) from humans (HsPiC, SLC25A3), yeast (ScPiC), A. gambiae (AgPiC), A. aegypti (AaPiC,) and D. melanogaster (DmPiC). Sequence alignments and accession numbers are included in Fig. S1. (B) Schematic representation of the AgMC1 protein sequence coding for three mitochondrial carrier domains (mito carr, top panel) highlighted in blue, green and red, and of the predicted secondary structure (bottom panel), consisting of six transmembrane domains (H1 to H6), three matrix domains, (M1 to M3), and cytosolic domains. (E) Predicted tertiary structure based on the amino acid sequence of the AgMC1 based on the known structure of bovine ADP/ATP adenine nucleotide translocator. Ribbon diagram of the predicted structure of AgMC1 from a lateral view (left), or viewed from either the matrix (top right) or intermembrane space side of the mitochondrial membrane (bottom right).

Mentions: Previous studies showed that expression of some genes related to the mitochondrial electron transport chain are induced in the Plasmodium-resistant A. gambiae (L3-5) refractory mosquito strain [8], [34], and that this strain has a higher rate of mitochondrial electron leak, suggesting that differences in mitochondrial metabolism affect mosquito susceptibility to Plasmodium infection [34]. We decided to investigate the potential role of AgMC1 in the mosquito redox balance and susceptibility to infection because some members of the solute carrier family are known to promote mitochondrial uncoupling and reduce ROS production [24], [30]–[32] and the AgMC1 gene is located in Chr 2 division 7B, a chromosomal region in A. gambiae that has been associated with the refractory phenotype [40]. A phylogenetic tree was built based on the sequence alignment of the deduced amino acid sequence of AgMC1 (accession number AGAP001297-RA) with mitochondrial transporters from different species (Figure 1A, Figure S1 and Table S1). AgMC1 has the highest homology to putative ortholog genes in Aedes aegypti (87% homology) and Drosophila melanogaster (72%), and clusters with the mammalian SLC25 family members 39 (60%) and 40 (64%) and the yeast manganese trafficking protein 1 (MTM) (48%) [41](37). SLC25 transporters share three conserved domains of approximately 100 amino acids that are the signature feature of mitochondrial carriers (Figure 1B, top). The predicted secondary structure of AgMC1 is shown as a schematic diagram in Figure 1B (bottom) and follows the same color scheme (blue, green, and red) as the linear diagram. It consists of six predicted transmembrane domains (H1-H6) joined together by the mitochondrial matrix (M1–M3) and cytosolic domains. Each mitochondrial carrier domain comprises a set of two transmembrane helixes and one matrix loop.


Mitochondrial reactive oxygen species modulate mosquito susceptibility to Plasmodium infection.

Gonçalves RL, Oliveira JH, Oliveira GA, Andersen JF, Oliveira MF, Oliveira PL, Barillas-Mury C - PLoS ONE (2012)

Anopheles gambiae mitochondrial carrier 1 (AgMC1) phylogeny and predicted structure.(A) Phylogenetic tree based on the sequence alignment of the deduced amino acid sequence of AgMC1 (AGAP001297-PA) and the putative mitochondrial carriers from A. aegypti (AaMC1), D. melanogaster (DmMC1), human mitochondrial carriers HsSLC25A-39 and SLC25A-40 and yeast manganese trafficking factor for mitochondrial (ScMTM1); uncoupling proteins from humans (HsUCP), A. gambiae (AgUCP), A. aegypti (AaUCP) and D. melanogaster (DmUCP); putative adenine nucleotide translocators (ANT) from humans (HsANT, SLC25A6), yeast (ScANT), A. gambiae (AgANT) A. aegypti (AaANT), and D. melanogaster (DmANT); putative phosphate carriers (PiC) from humans (HsPiC, SLC25A3), yeast (ScPiC), A. gambiae (AgPiC), A. aegypti (AaPiC,) and D. melanogaster (DmPiC). Sequence alignments and accession numbers are included in Fig. S1. (B) Schematic representation of the AgMC1 protein sequence coding for three mitochondrial carrier domains (mito carr, top panel) highlighted in blue, green and red, and of the predicted secondary structure (bottom panel), consisting of six transmembrane domains (H1 to H6), three matrix domains, (M1 to M3), and cytosolic domains. (E) Predicted tertiary structure based on the amino acid sequence of the AgMC1 based on the known structure of bovine ADP/ATP adenine nucleotide translocator. Ribbon diagram of the predicted structure of AgMC1 from a lateral view (left), or viewed from either the matrix (top right) or intermembrane space side of the mitochondrial membrane (bottom right).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3399787&req=5

pone-0041083-g001: Anopheles gambiae mitochondrial carrier 1 (AgMC1) phylogeny and predicted structure.(A) Phylogenetic tree based on the sequence alignment of the deduced amino acid sequence of AgMC1 (AGAP001297-PA) and the putative mitochondrial carriers from A. aegypti (AaMC1), D. melanogaster (DmMC1), human mitochondrial carriers HsSLC25A-39 and SLC25A-40 and yeast manganese trafficking factor for mitochondrial (ScMTM1); uncoupling proteins from humans (HsUCP), A. gambiae (AgUCP), A. aegypti (AaUCP) and D. melanogaster (DmUCP); putative adenine nucleotide translocators (ANT) from humans (HsANT, SLC25A6), yeast (ScANT), A. gambiae (AgANT) A. aegypti (AaANT), and D. melanogaster (DmANT); putative phosphate carriers (PiC) from humans (HsPiC, SLC25A3), yeast (ScPiC), A. gambiae (AgPiC), A. aegypti (AaPiC,) and D. melanogaster (DmPiC). Sequence alignments and accession numbers are included in Fig. S1. (B) Schematic representation of the AgMC1 protein sequence coding for three mitochondrial carrier domains (mito carr, top panel) highlighted in blue, green and red, and of the predicted secondary structure (bottom panel), consisting of six transmembrane domains (H1 to H6), three matrix domains, (M1 to M3), and cytosolic domains. (E) Predicted tertiary structure based on the amino acid sequence of the AgMC1 based on the known structure of bovine ADP/ATP adenine nucleotide translocator. Ribbon diagram of the predicted structure of AgMC1 from a lateral view (left), or viewed from either the matrix (top right) or intermembrane space side of the mitochondrial membrane (bottom right).
Mentions: Previous studies showed that expression of some genes related to the mitochondrial electron transport chain are induced in the Plasmodium-resistant A. gambiae (L3-5) refractory mosquito strain [8], [34], and that this strain has a higher rate of mitochondrial electron leak, suggesting that differences in mitochondrial metabolism affect mosquito susceptibility to Plasmodium infection [34]. We decided to investigate the potential role of AgMC1 in the mosquito redox balance and susceptibility to infection because some members of the solute carrier family are known to promote mitochondrial uncoupling and reduce ROS production [24], [30]–[32] and the AgMC1 gene is located in Chr 2 division 7B, a chromosomal region in A. gambiae that has been associated with the refractory phenotype [40]. A phylogenetic tree was built based on the sequence alignment of the deduced amino acid sequence of AgMC1 (accession number AGAP001297-RA) with mitochondrial transporters from different species (Figure 1A, Figure S1 and Table S1). AgMC1 has the highest homology to putative ortholog genes in Aedes aegypti (87% homology) and Drosophila melanogaster (72%), and clusters with the mammalian SLC25 family members 39 (60%) and 40 (64%) and the yeast manganese trafficking protein 1 (MTM) (48%) [41](37). SLC25 transporters share three conserved domains of approximately 100 amino acids that are the signature feature of mitochondrial carriers (Figure 1B, top). The predicted secondary structure of AgMC1 is shown as a schematic diagram in Figure 1B (bottom) and follows the same color scheme (blue, green, and red) as the linear diagram. It consists of six predicted transmembrane domains (H1-H6) joined together by the mitochondrial matrix (M1–M3) and cytosolic domains. Each mitochondrial carrier domain comprises a set of two transmembrane helixes and one matrix loop.

Bottom Line: Mitochondria perform multiple roles in cell biology, acting as the site of aerobic energy-transducing pathways and as an important source of reactive oxygen species (ROS) that modulate redox metabolism.AgMC1 silencing reduces mitochondrial membrane potential, resulting in increased proton-leak and uncoupling of oxidative phosphorylation.These metabolic changes reduce midgut ROS generation and increase A. gambiae susceptibility to Plasmodium infection.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, United States of America.

ABSTRACT

Background: Mitochondria perform multiple roles in cell biology, acting as the site of aerobic energy-transducing pathways and as an important source of reactive oxygen species (ROS) that modulate redox metabolism.

Methodology/principal findings: We demonstrate that a novel member of the mitochondrial transporter protein family, Anopheles gambiae mitochondrial carrier 1 (AgMC1), is required to maintain mitochondrial membrane potential in mosquito midgut cells and modulates epithelial responses to Plasmodium infection. AgMC1 silencing reduces mitochondrial membrane potential, resulting in increased proton-leak and uncoupling of oxidative phosphorylation. These metabolic changes reduce midgut ROS generation and increase A. gambiae susceptibility to Plasmodium infection.

Conclusion: We provide direct experimental evidence indicating that ROS derived from mitochondria can modulate mosquito epithelial responses to Plasmodium infection.

Show MeSH
Related in: MedlinePlus