This Article Full Text Full Text (PDF) Supplemental material Other Versions of this Article: JVI.02651-07v1 82/10/4774    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Copyright Information Books from ASM Press MicrobeWorld Google Scholar Articles by Gholami, A. Articles by Bourhy, H. PubMed PubMed Citation Articles by Gholami, A. Articles by Bourhy, H.

Mitochondrial Dysfunction in Lyssavirus-Induced Apoptosis ^,

Alireza Gholami,^1,# Raïd Kassis,^1,# Eléonore Real,^2, Olivier Delmas,¹ Stéphanie Guadagnini,³ Florence Larrous,¹ Dorothée Obach,¹ Marie-Christine Prevost,³ Yves Jacob,² and Hervé Bourhy^1*

Institut Pasteur, Unité Postulante de Recherche et d'Expertise Dynamique des Lyssavirus et Adaptation à l'Hôte, 75724 Paris Cedex 15, France,¹ Institut Pasteur, Unité Postulante de Génétique, Papillomavirus et Cancer Humain, 75724 Paris Cedex 15, France,² Institut Pasteur, Plateforme de Microscopie Ultrastructurale, 75724 Paris Cedex 15, France³

Received 13 December 2007/ Accepted 22 February 2008

Lyssaviruses are highly neurotropic viruses associated with neuronal apoptosis. Previous observations have indicated that the matrix proteins (M) of some lyssaviruses induce strong neuronal apoptosis. However, the molecular mechanism(s) involved in this phenomenon is still unknown. We show that for Mokola virus (MOK), a lyssavirus of low pathogenicity, the M (M-MOK) targets mitochondria, disrupts the mitochondrial morphology, and induces apoptosis. Our analysis of truncated M-MOK mutants suggests that the information required for efficient mitochondrial targeting and dysfunction, as well as caspase-9 activation and apoptosis, is held between residues 46 and 110 of M-MOK. We used a yeast two-hybrid approach, a coimmunoprecipitation assay, and confocal microscopy to demonstrate that M-MOK physically associates with the subunit I of the cytochrome c (cyt-c) oxidase (CcO) of the mitochondrial respiratory chain; this is in contrast to the M of the highly pathogenic Thailand lyssavirus (M-THA). M-MOK expression induces a significant decrease in CcO activity, which is not the case with M-THA. M-MOK mutations (K77R and N81E) resulting in a similar sequence to M-THA at positions 77 and 81 annul cyt-c release and apoptosis and restore CcO activity. As expected, the reverse mutations, R77K and E81N, introduced in M-THA induce a phenotype similar to that due to M-MOK. These features indicate a novel mechanism for energy depletion during lyssavirus-induced apoptosis.

Published ahead of print on 5 March 2008.

Supplemental material for this article may be found at http://jvi.asm.org/.

^# A.G. and R.K. contributed equally to this study.

Present address: Laboratory of Neurogenetics and Behavior, The Rockefeller University, New York, NY 10065.