Sustained Activation of Akt Elicits Mitochondrial Dysfunction to Block Plasmodium falciparum Infection in the Mosquito Host

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.

PGC-1α regulates the cell cycle through ATP and ROS in CH1 cells

“…S2). PGC-1α promotes mitochondrial biogenesis through expression of mitochondrial proteins and activation of p38/MAPK pathway (Acín-Pérez et al, 2008;Luckhart et al, 2013). These results confirmed that PGC-1α has an important role in prompting ATP production and clearing excessive ROS, and mitochondrial respiratory supercomplexes also enhance ATP and decrease ROS through structure variant, so we suggested that PGC-1α may be a positive regulator of mitochondrial respiratory supercomplex formation, but the mechanism remains unclear.…”

Genome analysis of a major urban malaria vector mosquito, Anopheles stephensi

“…number of studies have demonstrated the importance of these genes or pathways in mosquito defense against parasites or viruses [16][17][18][19][20][29][30][31]. Manual analysis showed overall agreement with the automated annotation and improved the gene models in some cases (Additional file 2).…”

“…Our understanding of the interactions between An. stephensi and the malaria parasites is rapidly improving [15][16][17][18][19][20]. Thus An.…”

Plasmodium falciparum evades mosquito immunity by disrupting JNK-mediated apoptosis of invaded midgut cells

“…Activation of FOXO has also been shown to decrease mitochondrial and cytoplasmic antioxidants (43), so it is possible that silencing FOXO may reduce midgut oxidative stress by increasing the level of antioxidants, and this would be beneficial to the parasite. Interestingly, activation of the same pathway in the absence of Pfs47, when JNK signaling is active, triggers a strong apoptotic response that greatly limits infection.…”