Charge of the mito brigade. Focus on “Changes in mitochondrial surface charge mediate recruitment of signaling molecules during apoptosis”

Abstract

the role of mitochondria as the foci of apoptotic signaling events in physiological and pathological conditions is now well-established (12). Multiple studies have demonstrated the recruitment of various cytosolic effector proteins, such as caspase-8, Bax, and Bak, to the outer membrane surface of mitochondria in apoptotic cells. Other reports have documented the redistribution of pro-apoptotic proteins, such as cytochrome c and Smac/Diablo, from the intermembrane space to the mitochondrial outer membrane (MOM) or the cytosol. The assembly of these newly recruited or transferred proteins into apoptotic signaling complexes, such as the Bax/Bak-based pores that mediate MOM permeabilization, has also been extensively characterized. Although the mechanisms by which apoptotic effector proteins recognize the MOM as a specific subcellular platform remain incompletely understood, recent studies have identified cardiolipin (CL), a predominantly mitochondrial phospholipid, as a key “targeting” factor (4, 6, 13). Both tBid (the pro-apoptotic truncated form of Bid) and caspase-8 bind to CL and disruption of these CL-effector protein interactions markedly attenuates the progression of apoptosis. Notably, association of these pro-apoptotic proteins with CL can involve stereospecific sites such as the hairpin motif within tBid formed by its α-6 helix (αH6) domain but independent of its BH3 domain (5, 11). However, CL is also dianionic at physiological pH and thus contributes to the overall surface charge of membranes in which it is abundant. In this issue of AJP-Cell Physiol, Heit et al. (8) report that mitochondria rapidly gain negative surface charge, likely due to increased CL in the outer membrane, during the early phases of apoptosis. Based on CL neutralization approaches, this study from Grinstein's group supports a novel and mechanistically significant model wherein mitochondrial exposure of negatively charged CL facilitates the electrostatic recruitment of multiple cationic proteins required for the progression of critical apoptotic signaling events.