The modulation of inter-organelle cross-talk to control apoptosis.
Mitochondria fulfill a wide array of functions dedicated to the energetic metabolism as well as the control of cell death. These functions imply that mitochondria can be activated by a variety of signals and can integrate them to trigger a process called mitochondrial membrane permeabilization (MMP), which induces the ultimate events of apoptosis. MMP consists in a sudden increase in the permeability of mitochondrial membrane that results in the release of critical proapoptotic intermembrane space effectors into the cytosol such as cytochrome c, apoptosis-inducing factor (AIF), Smac/Diablo, Endo G, and pro-caspases. In many models of apoptosis, mitochondrial translocation of proteins and/or lipids concomitantly with alterations of the intracellular milieu has been shown to activate MMP. This applies to tumor suppressors of the Bax/Bcl-2 family (Bax, Bad, Bid, Bim), several protein kinases (Akt, ASK1, hexokinase), p53, NF-kappaB, and nuclear orphan receptors such as TR3/Nur77. After mitochondrial membrane association, these proteins target constitutive mitochondrial proteins including the permeability transition pore complex (PTPC), Bcl-X(L), HSP70, and/or the lipid interphase. Subsequently, they switch their vital function into a lethal function to promote membrane permeabilization and protein release. In this review, we will describe some general rules of inter-organelle cross-talk activating MMP and will review selected examples of pro-apoptotic protein translocation. Finally, we will propose new pharmacological strategies to modulate this process in a therapeutic perspective.
Le Bras
Morgane
M
CNRS FRE 2445, Université de Versailles/St Quentin, 45, avenue des Etats-Unis, 78035 Versailles, France.
Rouy
Isabelle
I
Brenner
Catherine
C
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006801:Humans; D024101:Mitochondrial Proteins / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D015388:Organelles / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D051020:bcl-X Protein / Q000378:metabolism
D051033:Apoptosis Inducing Factor; D051017:Apoptosis Regulatory Proteins; D024101:Mitochondrial Proteins; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D018160:Receptors, Cytoplasmic and Nuclear; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D051020:bcl-X Protein; D020169:Caspases