Limits...
Sustained activation of Akt elicits mitochondrial dysfunction to block Plasmodium falciparum infection in the mosquito host.

Luckhart S, Giulivi C, Drexler AL, Antonova-Koch Y, Sakaguchi D, Napoli E, Wong S, Price MS, Eigenheer R, Phinney BS, Pakpour N, Pietri JE, Cheung K, Georgis M, Riehle M - PLoS Pathog. (2013)

Bottom Line: Despite an apparent increase in mitochondrial biogenesis in young females (3 d), energy deficiencies were apparent as decreased oxidative phosphorylation and increased [AMP]/[ATP] ratios.Hence, Akt-induced changes in mitochondrial dynamics perturb midgut homeostasis to enhance parasite resistance and decrease mosquito infective lifespan.Further, quality control of mitochondrial function in the midgut is necessary for the maintenance of midgut health as reflected in energy homeostasis and tissue repair and renewal.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Microbiology and Immunology, School of Medicine, University of California, Davis, Davis, California, United States of America. sluckhart@ucdavis.edu

ABSTRACT
The overexpression of activated, myristoylated Akt in the midgut of female transgenic Anopheles stephensi results in resistance to infection with the human malaria parasite Plasmodium falciparum but also decreased lifespan. In the present study, the understanding of mitochondria-dependent midgut homeostasis has been expanded to explain this apparent paradox in an insect of major medical importance. Given that Akt signaling is essential for cell growth and survival, we hypothesized that sustained Akt activation in the mosquito midgut would alter the balance of critical pathways that control mitochondrial dynamics to enhance parasite killing at some cost to survivorship. Toxic reactive oxygen and nitrogen species (RNOS) rise to high levels in the midgut after blood feeding, due to a combination of high NO production and a decline in FOXO-dependent antioxidants. Despite an apparent increase in mitochondrial biogenesis in young females (3 d), energy deficiencies were apparent as decreased oxidative phosphorylation and increased [AMP]/[ATP] ratios. In addition, mitochondrial mass was lower and accompanied by the presence of stalled autophagosomes in the posterior midgut, a critical site for blood digestion and stem cell-mediated epithelial maintenance and repair, and by functional degradation of the epithelial barrier. By 18 d, the age at which An. stephensi would transmit P. falciparum to human hosts, mitochondrial dysfunction coupled to Akt-mediated repression of autophagy/mitophagy was more evident and midgut epithelial structure was markedly compromised. Inhibition of RNOS by co-feeding of the nitric-oxide synthase inhibitor L-NAME at infection abrogated Akt-dependent killing of P. falciparum that begins within 18 h of infection in 3-5 d old mosquitoes. Hence, Akt-induced changes in mitochondrial dynamics perturb midgut homeostasis to enhance parasite resistance and decrease mosquito infective lifespan. Further, quality control of mitochondrial function in the midgut is necessary for the maintenance of midgut health as reflected in energy homeostasis and tissue repair and renewal.

Show MeSH

Related in: MedlinePlus

Over-expression of myrAKT was associated with changes in midgut mitochondria number and size.The number and size of mitochondria in the posterior midgut of myrAkt TG and NTG mosquitoes were determined for young (3 d) and old (18 d) mosquitoes within 85.90 µm of the brush border. (A) Average mitochondrial size was significantly decreased in midguts of 18 d old HM females compared to 18 d NTG and to 3 d HM. (B, C) The total number of mitochondria and mitochondrial density was significantly lower in 3 d HM mosquitoes relative to 3 d HT. In addition, the number and density of mitochondria significantly increased as the HM mosquitoes aged. (D) Total mitochondria content (percent area occupied by mitochondria) was significantly decreased in 18 d HT and HM mosquitoes and in 3 d HM mosquitoes relative to NTG controls and 3 d HT mosquitoes. Measurements from 5 midguts for each 3 d genotype and 4 midguts for each 18 d genotype were analyzed using a two-way ANOVA followed by Tukey-Kramer HSD test. Different letters indicate significant differences (alpha = 0.05).
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3585164&req=5

ppat-1003180-g005: Over-expression of myrAKT was associated with changes in midgut mitochondria number and size.The number and size of mitochondria in the posterior midgut of myrAkt TG and NTG mosquitoes were determined for young (3 d) and old (18 d) mosquitoes within 85.90 µm of the brush border. (A) Average mitochondrial size was significantly decreased in midguts of 18 d old HM females compared to 18 d NTG and to 3 d HM. (B, C) The total number of mitochondria and mitochondrial density was significantly lower in 3 d HM mosquitoes relative to 3 d HT. In addition, the number and density of mitochondria significantly increased as the HM mosquitoes aged. (D) Total mitochondria content (percent area occupied by mitochondria) was significantly decreased in 18 d HT and HM mosquitoes and in 3 d HM mosquitoes relative to NTG controls and 3 d HT mosquitoes. Measurements from 5 midguts for each 3 d genotype and 4 midguts for each 18 d genotype were analyzed using a two-way ANOVA followed by Tukey-Kramer HSD test. Different letters indicate significant differences (alpha = 0.05).

Mentions: Quantitative morphometric analysis of mitochondria in the posterior midgut revealed a significant decrease in the average size of mitochondria in midguts from 18 d HM females compared to similarly aged NTG females (by 47%, P<0.05; Fig. 5A). Midguts from 18 d HT also showed a decrease in average mitochondrial size (33% relative to NTGs) although this was not significantly different from 18 d NTG controls. In contrast to mitochondrial size, the number of mitochondria per µm2 of midgut and the total number of mitochondria per midgut decreased by 37% and 36% respectively in 3 d HM compared to NTG females; however, these decreases were not significant (Figs. 5B, C). The total of number of mitochondria per µm2 and the total number of mitochondria per midgut in 3 d HM were significantly lower than 3 d HT TG (45% decrease; P<0.05).


Sustained activation of Akt elicits mitochondrial dysfunction to block Plasmodium falciparum infection in the mosquito host.

Luckhart S, Giulivi C, Drexler AL, Antonova-Koch Y, Sakaguchi D, Napoli E, Wong S, Price MS, Eigenheer R, Phinney BS, Pakpour N, Pietri JE, Cheung K, Georgis M, Riehle M - PLoS Pathog. (2013)

Over-expression of myrAKT was associated with changes in midgut mitochondria number and size.The number and size of mitochondria in the posterior midgut of myrAkt TG and NTG mosquitoes were determined for young (3 d) and old (18 d) mosquitoes within 85.90 µm of the brush border. (A) Average mitochondrial size was significantly decreased in midguts of 18 d old HM females compared to 18 d NTG and to 3 d HM. (B, C) The total number of mitochondria and mitochondrial density was significantly lower in 3 d HM mosquitoes relative to 3 d HT. In addition, the number and density of mitochondria significantly increased as the HM mosquitoes aged. (D) Total mitochondria content (percent area occupied by mitochondria) was significantly decreased in 18 d HT and HM mosquitoes and in 3 d HM mosquitoes relative to NTG controls and 3 d HT mosquitoes. Measurements from 5 midguts for each 3 d genotype and 4 midguts for each 18 d genotype were analyzed using a two-way ANOVA followed by Tukey-Kramer HSD test. Different letters indicate significant differences (alpha = 0.05).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3585164&req=5

ppat-1003180-g005: Over-expression of myrAKT was associated with changes in midgut mitochondria number and size.The number and size of mitochondria in the posterior midgut of myrAkt TG and NTG mosquitoes were determined for young (3 d) and old (18 d) mosquitoes within 85.90 µm of the brush border. (A) Average mitochondrial size was significantly decreased in midguts of 18 d old HM females compared to 18 d NTG and to 3 d HM. (B, C) The total number of mitochondria and mitochondrial density was significantly lower in 3 d HM mosquitoes relative to 3 d HT. In addition, the number and density of mitochondria significantly increased as the HM mosquitoes aged. (D) Total mitochondria content (percent area occupied by mitochondria) was significantly decreased in 18 d HT and HM mosquitoes and in 3 d HM mosquitoes relative to NTG controls and 3 d HT mosquitoes. Measurements from 5 midguts for each 3 d genotype and 4 midguts for each 18 d genotype were analyzed using a two-way ANOVA followed by Tukey-Kramer HSD test. Different letters indicate significant differences (alpha = 0.05).
Mentions: Quantitative morphometric analysis of mitochondria in the posterior midgut revealed a significant decrease in the average size of mitochondria in midguts from 18 d HM females compared to similarly aged NTG females (by 47%, P<0.05; Fig. 5A). Midguts from 18 d HT also showed a decrease in average mitochondrial size (33% relative to NTGs) although this was not significantly different from 18 d NTG controls. In contrast to mitochondrial size, the number of mitochondria per µm2 of midgut and the total number of mitochondria per midgut decreased by 37% and 36% respectively in 3 d HM compared to NTG females; however, these decreases were not significant (Figs. 5B, C). The total of number of mitochondria per µm2 and the total number of mitochondria per midgut in 3 d HM were significantly lower than 3 d HT TG (45% decrease; P<0.05).

Bottom Line: Despite an apparent increase in mitochondrial biogenesis in young females (3 d), energy deficiencies were apparent as decreased oxidative phosphorylation and increased [AMP]/[ATP] ratios.Hence, Akt-induced changes in mitochondrial dynamics perturb midgut homeostasis to enhance parasite resistance and decrease mosquito infective lifespan.Further, quality control of mitochondrial function in the midgut is necessary for the maintenance of midgut health as reflected in energy homeostasis and tissue repair and renewal.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Microbiology and Immunology, School of Medicine, University of California, Davis, Davis, California, United States of America. sluckhart@ucdavis.edu

ABSTRACT
The overexpression of activated, myristoylated Akt in the midgut of female transgenic Anopheles stephensi results in resistance to infection with the human malaria parasite Plasmodium falciparum but also decreased lifespan. In the present study, the understanding of mitochondria-dependent midgut homeostasis has been expanded to explain this apparent paradox in an insect of major medical importance. Given that Akt signaling is essential for cell growth and survival, we hypothesized that sustained Akt activation in the mosquito midgut would alter the balance of critical pathways that control mitochondrial dynamics to enhance parasite killing at some cost to survivorship. Toxic reactive oxygen and nitrogen species (RNOS) rise to high levels in the midgut after blood feeding, due to a combination of high NO production and a decline in FOXO-dependent antioxidants. Despite an apparent increase in mitochondrial biogenesis in young females (3 d), energy deficiencies were apparent as decreased oxidative phosphorylation and increased [AMP]/[ATP] ratios. In addition, mitochondrial mass was lower and accompanied by the presence of stalled autophagosomes in the posterior midgut, a critical site for blood digestion and stem cell-mediated epithelial maintenance and repair, and by functional degradation of the epithelial barrier. By 18 d, the age at which An. stephensi would transmit P. falciparum to human hosts, mitochondrial dysfunction coupled to Akt-mediated repression of autophagy/mitophagy was more evident and midgut epithelial structure was markedly compromised. Inhibition of RNOS by co-feeding of the nitric-oxide synthase inhibitor L-NAME at infection abrogated Akt-dependent killing of P. falciparum that begins within 18 h of infection in 3-5 d old mosquitoes. Hence, Akt-induced changes in mitochondrial dynamics perturb midgut homeostasis to enhance parasite resistance and decrease mosquito infective lifespan. Further, quality control of mitochondrial function in the midgut is necessary for the maintenance of midgut health as reflected in energy homeostasis and tissue repair and renewal.

Show MeSH
Related in: MedlinePlus