The BH3-only BID (BH3-interacting domain death agonist) protein has a critical function in the death-receptor pathway in the liver by triggering mitochondrial outer membrane permeabilization (MOMP). Here we show that MTCH2/MIMP (mitochondrial carrier homologue 2/Met-induced mitochondrial protein), a novel truncated BID (tBID)-interacting protein, is a surface-exposed outer mitochondrial membrane protein that facilitates the recruitment of tBID to mitochondria. Knockout of MTCH2/MIMP in embryonic stem cells and in mouse embryonic fibroblasts hinders the recruitment of tBID to mitochondria, the activation of Bax/Bak, MOMP, and apoptosis. Moreover, conditional knockout of MTCH2/MIMP in the liver decreases the sensitivity of mice to Fas-induced hepatocellular apoptosis and prevents the recruitment of tBID to liver mitochondria both in vivo and in vitro. In contrast, MTCH2/MIMP deletion had no effect on apoptosis induced by other pro-apoptotic Bcl-2 family members and no detectable effect on the outer membrane lipid composition. These loss-of-function models indicate that MTCH2/MIMP has a critical function in liver apoptosis by regulating the recruitment of tBID to mitochondria.

BID, a proapoptotic BCL-2 family member, plays an essential role in the tumor necrosis factor alpha (TNF-␣)/Fas death receptor pathway in vivo. Activation of the TNF-R1 receptor results in the cleavage of BID into truncated BID (tBID), which translocates to the mitochondria and induces the activation of BAX or BAK. In TNF-␣-activated FL5.12 cells, tBID becomes part of a 45-kDa cross-linkable mitochondrial complex. Here we describe the biochemical purification of this complex and the identification of mitochondrial carrier homolog 2 (Mtch2) as part of this complex. Mtch2 is a conserved protein that is similar to members of the mitochondrial carrier protein family. Our studies with mouse liver mitochondria indicate that Mtch2 is an integral membrane protein exposed on the surface of mitochondria. Using blue-native gel electrophoresis we revealed that in viable FL5.12 cells Mtch2 resides in a protein complex of ca. 185 kDa and that the addition of TNF-␣ to these cells leads to the recruitment of tBID and BAX to this complex. Importantly, this recruitment was partially inhibited in FL5.12 cells stably expressing BCL-X L . These results implicate Mtch2 as a mitochondrial target of tBID and raise the possibility that the Mtch2-resident complex participates in the mitochondrial apoptotic program.

Mitochondria play a pivotal role in the process of apoptosis. Alterations in mitochondrial structure and function during apoptosis are regulated by proteins of the BCL-2 family, however their exact mechanism of action is largely unknown. Mitochondrial carriers and pores play an essential role in maintaining the normal function of mitochondria, and BCL-2 family members were shown to interact with several mitochondrial carriers/pores and to affect their function. This review focuses on the involvement of several of these mitochondrial carriers/pores in the regulation of the mitochondrial death pathway.

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Iron deficiency induces accumulation of a transferrin-like protein, TTf, in plasma membranes of the halotolerant alga Dunaliella salina. In vivo iron binding and uptake studies provided evidence for the role of TTf in iron acquisition in Dunaliella. In this report, we characterized the iron binding activity of solubilized TTf, purified from plasma membrane vesicles of iron-starved cells. The characteristics of iron binding to TTf generally resembled those of animal transferrins (Tfs) in an obligatory requirement for bicarbonate as a co-ligand, specificity for ferric ions and pH dependence of both binding and release. Unlike animal Tfs, Fe binding activity of TTf was stimulated by high NaCl concentrations. The stimulation was not associated with changes in Fe binding affinity. The results unequivocally confirm the role of TTf in Fe binding and 2081 uptake in Dunaliella and demonstrate its uniqueness as a membraneassociated, salt-stimulated transferrin.