title: 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.
authors.affiliation: Department of Medical Microbiology and Immunology, School of Medicine, University of California, Davis, Davis, California, United States of America. sluckhart@ucdavis.edu
authors.forename: Shirley
authors.initials: S
authors.lastname: Luckhart
authors.forename: Cecilia
authors.initials: C
authors.lastname: Giulivi
authors.forename: Anna L
authors.initials: AL
authors.lastname: Drexler
authors.forename: Yevgeniya
authors.initials: Y
authors.lastname: Antonova-Koch
authors.forename: Danielle
authors.initials: D
authors.lastname: Sakaguchi
authors.forename: Eleonora
authors.initials: E
authors.lastname: Napoli
authors.forename: Sarah
authors.initials: S
authors.lastname: Wong
authors.forename: Mark S
authors.initials: MS
authors.lastname: Price
authors.forename: Richard
authors.initials: R
authors.lastname: Eigenheer
authors.forename: Brett S
authors.initials: BS
authors.lastname: Phinney
authors.forename: Nazzy
authors.initials: N
authors.lastname: Pakpour
authors.forename: Jose E
authors.initials: JE
authors.lastname: Pietri
authors.forename: Kong
authors.initials: K
authors.lastname: Cheung
authors.forename: Martha
authors.initials: M
authors.lastname: Georgis
authors.forename: Michael
authors.initials: M
authors.lastname: Riehle
mesh_terms: D000818:Animals; D000852:Anopheles / Q000469:parasitology*; D060467:Disease Resistance; D005260:Female; D041981:Gastrointestinal Tract / Q000378:metabolism / Q000469:parasitology; D006790:Host-Parasite Interactions; D006801:Humans; D019476:Insect Proteins / Q000096:biosynthesis; D016778:Malaria, Falciparum / Q000517:prevention & control*; D008297:Male; D008928:Mitochondria / Q000378:metabolism / Q000469:parasitology / Q000648:ultrastructure; D028361:Mitochondrial Diseases / Q000378:metabolism* / Q000469:parasitology; D010963:Plasmodium falciparum / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D019476:Insect Proteins; D051057:Proto-Oncogene Proteins c-akt