Kristi Norris
George Washington University
Richard Youle Laboratory, Biochemistry Section, SNB, NINDS

NIH Thesis Seminar
June 23, 2008 10:30 am
Building 35, room BB 1000 (Basement level in Bldg 35; Use  B pod elevators down to basement)
 
Title: Cellular effects of vMIA highlight shared machinery of apoptosis regulation and mitochondrial morphogenesis

Mitochondria are dynamic organelles, constantly undergoing the opposing processes of fusion and fission, and mitochondrial morphogenesis has been linked to both the metabolic state and health of the cell. Cell death, or apoptosis, is regulated at the mitochondria by the Bcl-2 family of proteins, which consists of both pro- and anti-apoptotic members. Apoptosis is an important host defense mechanism against viruses that can be subverted by viral gene products. Human cytomegalovirus encodes “viral mitochondria-localized inhibitor of apoptosis” (vMIA; pUL37x1), which targets to mitochondria where it functions as a potent cell death suppressor in part by binding to and inhibiting the pro-apoptotic Bcl-2 family member Bax. vMIA expression also dramatically alters mitochondrial morphology, causing the fragmentation of these organelles, a phenotype typically associated with cell death. The mechanism by which vMIA functions to block cytochrome c release from the mitochondria has not been fully elucidated. As Bax and Bak have been shown to play a role in regulating mitochondrial fusion in healthy cells and vMIA is able to interact with and inhibit the pro-apoptotic function of both these proteins, vMIA may fragment mitochondria through inhibition of Bax and Bak maintenance of mitochondrial morphology in addition to blocking their pro-apoptotic activity. Bax and Bak have been proposed to regulate mitochondrial fusion through the large GTPase Mfn2, a key mitochondrial fusion protein. vMIA also interacts with Mfn2, and this interaction is independent of both Bax and Bak, which may bind both mitofusins and vMIA. Surprisingly, vMIA fails to inhibit apoptosis in cells lacking Mfn2. The lack of protection by vMIA in cells lacking Mfn2 suggests that neutralization of Bax and Bak activity by vMIA may be through the formation of a functional complex with Mfn2, providing new insights into the mechanism of apoptosis inhibition by vMIA. These results also indicate an essential role of Mfn2 in mediating apoptosis inhibition by vMIA, further connecting mitochondrial morphology machinery and apoptosis regulation.