Mitochondrion-targeted apoptosis regulators of viral origin q Patricia Boya, Thomas Roumier, Karine Andreau, Rosa-Ana Gonzalez-Polo, Naoufal Zamzami, Maria Castedo, and Guido Kroemer * Centre National de la Recherche Scientifique, UMR 8125, Institut Gustave Roussy, Pavillon de Recherche 1, 39, rue Camille Desmoulins, F-94805 Villejuif, France Received 15 January 2003 Abstract During coevolution with their hosts, viruses have ‘‘learned’’ to intercept or to activate the principal signal transducing pathways leading to cell death. A number of proteins from pathophysiologically relevant viruses are targeted to mitochondria and regulate (induce or inhibit) the apoptosis-associated permeabilization of mitochondrial membranes. Such proteins are encoded by human immunodeficiency virus 1, KaposiÕs sarcoma-associated herpesvirus, human T-cell leukemia virus-1, hepatitis B virus, cytomega- lovirus, and Epstein Barr virus, among others. Within mitochondria, such apoptosis regulators from viral origin can target distinct proteins from the Bcl-2 family and the permeability transition pore complex including the adenine nucleotide translocase, cyclo- philin D, the voltage-dependent anion channel, and the peripheral benzodiazepine receptor. Thus, viral proteins can regulate apoptosis at the mitochondrial level by acting on a variety of different targets. Ó 2003 Elsevier Science (USA). All rights reserved. Keywords: Apoptosis; Caspases; Cell death; Mitochondria Apoptosis is associated with a complete permeabili- zation of the outer mitochondrial membrane (OM) leading to the release of intermembrane proteins into the cytosol. Such proteins include caspase activators (e.g., cytochrome c and Smac/DIABLO) as well as caspase- independent death effectors (e.g., AIF and endonuclease G) [1,2]. Mitochondria also undergo a partial and sometimes transient permeabilization of the inner mi- tochondrial membrane (IM), resulting in the loss of re- spiratory function [3]. The molecular mechanisms of mitochondrial membrane permeabilization (MMP) probably depend on the exact signal transduction pathway responsible for apoptosis induction. MMP is induced by a myriad of different pro-apoptotic mole- cules including Ca 2þ , reactive oxygen species, nitric ox- ide, fatty acids, ganglioside GD3, pro-apoptotic proteins from the Bcl-2 family, some stress kinases, and dozens of different xenobiotics including a number of different anti-cancer agents [4]. Thus, mitochondria integrate and unify different apoptotic pathways into one common final pathway culminating in apoptotic demise. Viruses subvert the apoptotic machinery of their hosts with the dual aim of increasing viral production and viral spread [5]. Therefore, they tend to inhibit apoptosis during early stages of the life cycle when replication requires a living host cell. Later on, some viruses may stimulate apoptosis with the aim of facili- tating viral spreading and subverting the hostÕs immune response. Viral proteins have been described to target a plethora of apoptosis regulators including caspases and the death-inducing signaling complex (DISC) formed after cross-linking of CD95-like cell surface receptors. More recently, it has become clear that proteins from infectious microorganisms can also target mitochondria, either to inhibit MMP (and thus to suppress apoptosis) or to induce MMP (and thus to trigger apoptosis) [6]. This review will summarize recent knowledge accumu- lating in this flourishing field. Biochemical and Biophysical Research Communications 304 (2003) 575–581 www.elsevier.com/locate/ybbrc BBRC q Abbreviations: ANT, adenine nucleotide translocase; Cyp D, cyclophilin D; HIV-1, human immunodeficiency virus 1; HTLV-1, human T-cell leukemia virus 1; IM, inner membrane; MMP, mito- chondrial membrane permeabilization; OM, outer membrane; PBR, peripheral benzodiazepine receptor; PTPC, permeability transition pore complex; VDAC, voltage-dependent anion channel; vMIA, viral mitochondrial inhibitor of apoptosis. * Corresponding author. Fax: +33-1-42-11-60-47. E-mail address: kroemer@igr.fr (G. Kroemer). 0006-291X/03/$ - see front matter Ó 2003 Elsevier Science (USA). All rights reserved. doi:10.1016/S0006-291X(03)00630-2