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A BID on Mitochondria with MTCH2 Cell Research (2010) 20:863-865. npg © 2010 IBCB, SIBS, CAS All rights reserved 1001-0602/10 $ 32.00 RESEARCH HIGHLIGHT www.nature.com/cr A BID on mitochondria with MTCH2 Sara Cogliati1, Luca Scorrano1, 2 1Dulbecco-Telethon Institute, Venetian Institute of Molecular Medicine, Via Orus 2, 35129 Padova, Italy; 2Department of Cell Physiology and Metabolism, University of Geneva, 1 Rue M. Servet, 1206 Geneve, Switzerland Cell Research (2010) 20: 863-865. doi:10.1038/cr.2010.100; published online 13 July 2010 Apoptosis is a key process for tis- It is fundamental in embryonic develop- of the effector caspases requires the mi- sue homeostasis and renewal. Its dys- ment, organogenesis and in maintaining tochondrial amplification loop. To this regulation is implicated in most human tissue homeostasis in adult organisms. end pro-caspase 8 is recruited on mito- diseases, from cancer to neurodegenera- Impairment of apoptotic pathways chondria where it binds to cardiolipin tion. Apoptosis is triggered by stimuli leads to cancer, while their upregula- [3]. There, after self activation induced that damage the internal structures tion results in degenerative disease. In by proximity, it cleaves the proapoptotic of the cell, or by specialized “death” mammalian cells, there are two main BH3-only member, BID, and activate it. receptors on its surface. In certain cell pathways downstream of death signals The active form, christened truncated types, Bid, a “BH3-only” member of that are linked in certain cell types: the BID (tBID) on the surface of mitochon- the Bcl-2 family of death regulators “death receptor” pathway triggered by dria, triggers the release of cytochrome integrates these two pathways at the extrinsic stimuli (e.g. Fas, TNFα) and c by causing oligomerization of BAX mitochondrial level. Despite years of the mitochondrial pathway triggered and BAK that results in outer membrane intense research, the mechanisms by by intrinsic death stimuli (e.g. DNA permeabilization [2] and by inducing which Bid translocates to mitochondria damage). Both culminate in the activa- Opa1-dependent cristae remodelling remain unclear. A recent study by Gross tion of caspases, cysteine proteases that [4-6]. The importance of tBID in the and colleagues sheds new light on this cleave a number of substrates involved Fas death pathway is well established, process [1]. They identified MTCH2 as in maintenance of cytoskeletal and however the molecular mechanism a mitochondrial protein that interacts nuclear integrity, cell cycle progres- of tBID recruitment on mitochondria with Bid and whose ablation dramati- sion and DNA repair, resulting in the is still unknown and this has been an cally affects mitochondrial translocation orderly demise of the cell. Mitochondria area of intense investigation in the last of this BH3-only protein. Interestingly, participate in the competent activation years. Two main models have been put MTCH2 shares homology with mem- of caspases, by releasing cytochrome forward to explain the affinity of BID bers of the mitochondrial carrier family, c and additional apoptogenic factors for mitochondria: one postulates that but it is located on the outer membrane from the intermembrane space into the BID travels to mitochondria as a conse- of the organelle; and it was recently cytosol. Cytochrome c in complex with quence of its affinity for specific lipids, reported to be associated with increased Apaf-1 activates caspase 9 and other or of its specific lipidation; the other body mass index. Thus, this study not downstream “effector” caspases. The involves the existence of one or more only unveils how BID is targeted to key regulators of this apoptotic process specific receptors on the mitochondrial mitochondria during apoptosis, but also are proteins of the Bcl-2 family which surface that interact with tBID to as- opens interesting avenues to investigate orchestrate the signals leading to the sist its insertion in the mitochondrial the relationship between mitochondria, activation of effector caspases [2]. In membrane. apoptosis and control of metabolism. response to the activation of death The first model is supported by earli- Programmed cell death or apoptosis receptors, the apical pro-caspase 8 un- er studies that indicated how N-terminal is a conserved pathway in all metazoans. dergoes autoproteolytic activation. In myristoylation increases the affinity of type I cells, such as thymocytes, active tBID for the organelle [7]. In addition, caspase 8 directly cleaves the effector tBID binds to the phospholipid cardio- Correspondence: Luca Scorrano caspases 3 and 7, whereas in type II lipin (retrieved only in mitochondria), E-mail: [email protected] cells, such as hepatocytes, the activation which proved to be required for tBID npg 864 action [8]. Interestingly, cardiolipin on the outer mitochondrial membrane can Cell death receptor also function as a scaffold for caspase 8, which translocates to mitochondria where it produces locales of BID [3]. DISC In addition, the lipid composition of liposomes crucially modulated the ability of BID to permeabilize them, further substantiating a role for lipids in the action (and the targeting) of tBID Pro-caspase 8 [9]. In the second model, biochemical studies have substantiated a role for several mitochondrial proteins as recep- tors for tBID recruitment [10]. These BID MTCH2/MIMP include VDAC, as well as components Caspase 8 tBID of the mitochondrial protein import BAX/K BAX/K BAX/K BAX/K BAX/K BAX/K BAX/K machinery, like TOM20, 22, 70 and 40 BAX/K BAX/K BAX/K (reviewed in [11]), however, conclusive evidence for their role in this process is Cytochrome c often lacking. In a recent paper, Zaltsman et al. provide new important insights into the mechanism of recruitment of tBID on mitochondria. They define MTCH2/ MIMP as a receptor for tBID on mito- chondria and establish, using animal models, the importance of MTCH2/ Figure 1 The recruitment of tBID on mitochondria is mediated by the novel MIMP protein in Fas-induced hepato- target protein MTCH2/MIMP. The diagram depicts the sequence of events cellular apoptosis [1]. MTCH2/MIMP that occur in type II cells following an extrinsic death stimulus. Pro-caspase 8 is a protein of the mitochondrial carrier binds to cardiolipin (yellow) on mitochondria where it undergoes self-proteolytic family. In TNF-α treated cells, it resides activation to cleave BID. The active tBID is then recruited on mitochondria in a 185 kDa large complex that com- by MTCH2/MIMP. This in turn leads to oligomerization of BAX/BAK and cyto- chrome c release. prises also tBID and BAX [12]. This evidence raised the hypothesis that MTCH2/MIMP could be involved in the mitochondrial apoptotic program but esis, Zaltsman and coworkers assessed of Fas. Taken together, these results its role was not clear. Now, the paper of the role of MTCH2/MIMP in vivo. They clearly demonstrated that MTCH2/ Zaltsman et al. closes this gap. first generated conventional knockouts, MIMP protein is essential for the re- The first outstanding question that which were embryonically lethal when cruitment of tBID on mitochondria and Zaltsman et al. tackled in their work homozygous. They therefore created a it plays a fundamental role in the tBID- was the submitochondrial localization conditional gene knockout mouse by us- mediated cell death [1] (Figure 1). of MTCH2. Being a member of the car- ing the Cre/loxP system. When MTCH2 It has been demonstrated in vivo rier superfamily, the natural prediction is ablated, the cross-linkable complex that BID plays a key role in cell death would be that it was located in the inner tBID-MTCH2/MIMP is not detectable. induced by death-receptor ligands such membrane. However, using three differ- Moreover, cells lacking MTCH2 are less as Fas ligand. In particular it exerts an ent biochemical approaches the authors sensitive to apoptosis induced by tBID important role in Fas ligand-induced clearly demonstrate that MTCH2/MIMP and this defect is rescued by the reintro- apoptosis in hepatocytes [13]. Zalts- is in the outer membrane of the organ- duction of MTCH2/MIMP. The reduced man and coworkers analyzed whether elle. This result opened the possibility apoptosis is due to an impairment of loss of MTCH2/MIMP that abolished that MTCH2 participates in the steps of tBID accumulation in mitochondria, in vitro recruitment of tBID on mito- mitochondrial targeting of tBID during following stimuli that converge on this chondria could have significant effects apoptosis. In order to verify this hypoth- BH3-only protein, including activation on hepatocellular apoptosis in vivo. Cell Research | Vol 20 No 8 | August 2010 npg 865 They generated MTCH2/MIMP liver- polymorphic variants are associated 4 Cipolat S, Rudka T, Hartmann D, et specific knockout mice and assessed with increased body mass index. Among al. Mitochondrial rhomboid PARL ther sensitivity to Fas. The liver-specific them, MTCH2 was the only one whose regulates cytochrome c release during apoptosis via OPA1-dependent cristae knockout animals show less liver injury mRNA was not detected in the hypo- remodeling. Cell 2006; 126:163-175. and are more resistant to death than thalamus. This suggests that MTCH2 5 Frezza C, Cipolat S, Martins dB, et al. heterozygotes. In order to investigate could play roles in the regulation of OPA1 controls apoptotic cristae remod- the molecular mechanism of these ef- body mass in the periphery, as a regula- eling independently from mitochondri- fects, they analyzed the activation of tor of energy expenditure. Apoptosis has al fusion. Cell 2006; 126:177-189. caspases and the recruitment of tBID been previously linked to metabolism 6 Scorrano L, Ashiya M, Buttle K, et al. to mitochondria. The results clearly when the BH3-only protein BAD was A distinct pathway remodels mitochon- showed that in mice lacking MTCH2/ discovered to be a scaffold for enzymes drial cristae and mobilizes cytochrome c during apoptosis.
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