Human adenovirus type 5 infection alters mitochondrial membrane dynamics

Sammanfattning: Mitochondria are double-membrane organelles that orchestrate essential cellular functions including ATP synthesis, calcium homeostasis and apoptosis. Furthermore, mitochondria are effective stimulators of the innate immune system through the release of mitochondrial components into the cytosol. One such stimulus is mitochondrial DNA (mtDNA) which is recognized by receptors of the innate immune system, such as cGAS or TLR9 due to its resemblance to bacterial DNA. Several viruses have been shown to induce the release of mtDNA, including influenza virus and dengue virus. This thesis utilizes biochemical, qPCR and microscopy methods to study how human adenovirus type 5 (HAdV-C5) infection alters mitochondrial DNA and membrane dynamics. Results in this thesis reveal that also HAdV-C5 induces release of mtDNA into the cytosol, correlating with the expression of a specific viral structural protein during the late phase of infection. Notably, transient transfection of this viral protein is sufficient to release mtDNA into the cytosol. The viral protein harbors an amphipthatic helix whose putative functions are targeting of the viral protein to the mitochondria and altering the mitochondrial membrane integrity. Elimination of the Bax and Bak proteins reduces the viral protein-mediated mtDNA release. In addition, accumulation of the viral protein in mitochondria leads to the hyperpolarization of the inner mitochondrial membrane. Collectively, this thesis reveals novel interactions of HAdV-C5 infection with mitochondrial functions.