A BID on Mitochondria with MTCH2

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 receptors 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 mitochondria 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 cytochrome 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. Dev Cell 2002; MIMP in liver, caspase 8 was cleaved of glucose metabolism on the surface 2:55-67. but the recruitment of tBID to mito- of mitochondria, independently of its 7 Zha J, Weiler S, Oh KJ, Wei MC, Kors- chondria failed. This causes less activa- function in apoptosis [15]. However, meyer SJ. Posttranslational N-myris- tion of caspase 3 and consequently the in the case of MTCH2 it is not clear if toylation of BID as a molecular switch hepatocites are less prone to apoptosis the protein like BAD fulfils multiple for targeting mitochondria and apopto- after Fas stimulation. functions in independent pathways, or sis. Science 2000; 290:1761-1765. These results definitely confirmed if its role in apoptosis is key also for 8 Lutter M, Fang M, Luo X, et al. Cardi- olipin provides specificity for targeting that the MTCH2/MIMP protein plays a the regulation of body weight. In addi- of tBid to mitochondria. Nat Cell Biol fundamental role in the recruitment of tion, it might be interesting to address 2000; 2:754-761. tBID to mitochondria and thus playing a if MTCH2 participates in the regulation 9 Kuwana T, Mackey MR, Perkins G, et key role in the Fas death pathway. More- of body weight by impacting on mito- al. Bid, Bax, and lipids cooperate to over, this paper contributes to clarify chondrial function. Studies capitalizing form supramolecular openings in the the basal mechanism of interaction of on the use of the conditional knockout outer mitochondrial membrane. Cell tBID with the mitochondria. Thanks to animals generated by Zaltsman et al. 2002; 111:331-342. 10 Schafer B, Quispe J, Choudhary V, et the paper of Zaltmans and co-workers, will for sure help address these ques- al. Mitochondrial outer membrane pro- we now understand that the recruitment tions and place this protein in the broad teins assist Bid in Bax-mediated lipidic of tBID on mitochondria is at least par- context of integrated metabolism. pore formation. Mol Biol Cell 2009; tially orchestrated by a specific protein. 20:2276-2285. However, it should be mentioned that Acknowledgments 11 Ott M, Norberg E, Zhivotovsky B, Or- the ablation of MTCH2 is not able per renius S. Mitochondrial targeting of se to completely abrogate apoptosis, LS is a Senior Telethon Scientist of the tBid/Bax: a role for the TOM complex? suggesting that other proteinaceous and/ Dulbecco-Telethon Institute and supported by Cell Death Differ 2009; 16:1075-1082. 12 Grinberg M, Schwarz M, Zaltsman Y, or lipidic receptors exist and play a role The Italian Association for Cancer Research (AIRC), Telethon Italy. et al. Mitochondrial carrier homolog 2 in the targeting of BID to mitochondria. is a target of tBID in cells signaled to Thus, it would be interesting to ad- References die by tumor necrosis factor alpha. Mol dress if in cells lacking enzymes that Cell Biol 2005; 25:4579-4590. participate in cardiolipin remodelling, 13 Yin XM, Wang K, Gross A, et al. Bid- 1 Zaltsman Y, Shachnai L, Yivgi-Ohana deficient mice are resistant to Fas-in- like tafazzin [14], ablation of MTCH2 N, et al. MTCH2/MIMP is a major fa- duced hepatocellular apoptosis. Nature completely reduces it, substantiating cilitator of tBID recruitment to mito- 1999; 400:886-891. a model in which lipids and proteins chondria. Nat Cell Biol 2010; 12:553- 14 Xu Y, Malhotra A, Ren M, Schlame M. 562. cooperate to target BID. Alternatively, The enzymatic function of tafazzin. J 2 Danial NN, Korsmeyer SJ. Cell death: one can envision a role for cardiolipin Biol Chem 2006; 281:39217-39224. critical control points. Cell 2004; in targeting and/or assembly of MTCH2 15 Danial NN, Gramm CF, Scorrano L, 116:205-219. in the outer membrane. et al. BAD and glucokinase reside in a 3 Gonzalvez F, Schug ZT, Houtkooper mitochondrial complex that integrates Another interesting link is that RH, et al. Cardiolipin provides an es- glycolysis and apoptosis. Nature 2003; between MTCH2 and metabolism. sential activating platform for cas- 424:952-956. MTCH2 recently emerged from a genet- pase-8 on mitochondria. J Cell Biol ic screen as one of six new loci whose 2008; 183:681-696.