PerspectiveCell Biology

Mitochondrial Dynamics and Apoptosis—the ER Connection

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Science  31 Aug 2012:
Vol. 337, Issue 6098, pp. 1052-1054
DOI: 10.1126/science.1224709

Mitochondria are endosymbiotic organelles that were pivotal in the evolution of eukaryotic multicellular organisms, enabling cells, through production of adenosine 5′-triphosphate, to overcome a steep energetic barrier (1). Another essential feature of multicellularity is programmed cell death or apoptosis—a process in which mitochondria also play a critical role. During intrinsic apoptosis, a signaling platform assembles on mitochondria that in some organisms is harnessed to permeabilize the outer mitochondrial membrane and release proapoptotic proteins. Assembly of this platform is accompanied by dramatic changes in the dynamic behavior of mitochondria, which influence cell death. The dynamic properties of mitochondria are dependent on their division and fusion and govern the overall shape, connectedness, and distribution of mitochondria in cells. On page 1062 in this issue, Youle and van der Bliek (2) review the interplay between mitochondrial dynamics and mitochondrial quality-control and stress pathways. Here, we speculate on the role of mitochondrial division and fusion in the ultimate stress response, cell death. The recent discovery that the endoplasmic reticulum (ER), another ancient endomembrane organelle, actively participates in mitochondrial division has led to a new model linking mitochondrial dynamics and cell death. This suggests an unexpected convergence during evolution of mitochondria and ER—the two dominant endomembrane systems in eukaryotic cells that have previously been viewed as functionally distinct.

Mitochondrial division and fusion are mediated by the action of large self-assembling dynamin-related guanosine triphosphatases (DRPs) (3). Mitochondrial division is catalyzed by a single cytosolic DRP, DRP1, and fusion requires two integral membrane DRP families, MFN1/MFN2 and OPA1, which are distributed in the outer and inner mitochondrial membranes, respectively. DRP1 self-assembles into helical structures that wrap around mitochondria and coordinately divide the outer and inner membranes (46). Similarly, the self-assembly properties of mitochondrial fusion DRPs are also somehow harnessed for membrane tethering and lipid mixing of the outer and inner membranes (7, 8). In addition to their canonical roles in regulating mitochondrial structure, the mitochondrial division and fusion DRPs function in key quality-control and stress pathways. They impinge specifically on Bcl-2–dependent mitochondrial outer membrane permeabilization, which is required for apoptosis, suggesting that they directly link these two processes in the cell.

The exact mechanism by which mitochondrial DRPs and other mitochondrial shaping proteins influence outer membrane permeabilization is still a mystery. The best-characterized is the inhibitory role of OPA1, which is due in part to its regulation of the junctions positioned at the mouths of the internal mitochondrial compartments known as cristae, which act as gatekeepers in the release of proapoptotic proteins from the intermembrane space (9, 10). The positive regulatory role of DRP1 in mitochondrial outer membrane permeabilization depends on its recruitment to mitochondria. During apoptosis, DRP1 is massively recruited to the mitochondrial outer membrane where it assembles into foci, which mediate mitochondrial division, causing a dramatic fragmentation of the mitochondrial network. The proapoptotic Bcl-2 protein Bax behaves similarly to DRP1 during apoptosis; it is recruited to the mitochondrial outer membrane, where it inserts and oligomerizes to form foci that are functionally linked to outer membrane permeabilization. Under apoptotic conditions, DRP1 is found in foci with Bax on mitochondria (11). In healthy cells, MFN2 is also observed in foci on mitochondria and, similar to DRP1, under apoptotic conditions, is found in foci with Bax (11, 12). These apoptotic foci spatially mark mitochondrial constriction sites and mitochondrial tips, consistent with the idea that they are associated with the observed increase in mitochondrial division and fragmentation. However, extensive data show that mitochondrial fragmentation is not a key factor in mitochondrial outer membrane permeabilization and cell death, indicating that the role of DRP1 in regulating outer membrane permeabilization is independent of its role in mitochondrial division per se. What, then, are the molecular roles of DRP1, MFN2, and other components that regulate mitochondrial dynamics, in apoptosis?

ER-mitochondrial microdomains.

A model showing how ER-associated mitochondrial division (ERMD) creates microdomains that can be harnessed for diverse cellular functions. The ER associates with mitochondria, marking sites of future mitochondrial division. These sites create microdomains enriched in mitochondrial division components, such as DRP1 and Mff. The microdomains may be used under stress conditions to recruit and regulate the activation of proapoptotic Bcl-2 proteins like Bax to promote permeabilization of the mitochondrial outer membrane (MOMP) and the release of death mediators, such as cytochrome c (cyt c).

CREDIT: ADAPTED BY P. HUEY/SCIENCE

A clue to the functional importance of these striking cytological changes upon cell death, as well as the regulatory roles of mitochondrial dynamics components in mitochondrial outer membrane permeabilization, comes from the discovery that specialized ER tubules wrap around mitochondria and mark mitochondrial division sites (13). One likely role of ER-associated mitochondrial division (ERMD) is to create a mitochondrial constriction site or geometric “hot spot” for the assembly of the mitochondrial division dynamin helix. It is possible that during apoptosis, ERMD also plays a critical role in Bax-dependent mitochondrial outer membrane permeabilization (see the figure). Specifically, ERMD sites could represent an ER-mitochondria microdomain that is critical for Bax insertion and oligomerization. The existence of such microdomains is substantiated by the observation that the DRP1 receptor and effector, Mff, accumulates at sites of ER-mitochondrial contact in the absence of DRP1, providing a spatial mark for DRP1 recruitment to mitochondrial constriction sites (13). Microdomains generated at ER-mitochondrial contacts, called mitochondrial-associated membranes, have also been implicated in lipid and calcium exchange. The existence of specialized mitochondrial-associated membranes for Bax activation is supported by recent in vitro work demonstrating that sphingolipid metabolites derived from a non–mitochondrial membrane compartment directly stimulate the assembly and oligomerization of Bax in the mitochondrial outer membrane to promote permeabilization (14). In this context, an ER-mitochondrial microdomain would facilitate the shuttling of key lipid effectors of Bax.

Mitochondrial DRPs, and other mitochondrial and ER components, could both positively and negatively regulate mitochondrial outer membrane permeabilization by influencing the biogenesis and/or structure of the ERMD microdomain. The mitochondrial division and fusion DRPs are well suited to this role as they can assemble into an array of geometrically diverse membrane-associated scaffolds, which selectively recruit and spatially restrict lipid and protein effectors. Indeed, DRP1 may promote Bax oligomerization in vitro by stabilizing membrane tethering and promoting lipid mixing across membranes via hemifusion (15). In healthy cells, inactive soluble forms of Bax stimulate MFN2-dependent fusion (16). This finding, coupled with the localization of MFN2 with Bax in foci during apoptosis, suggests an MFN2-dependent mitochondrial outer membrane permeabilization regulatory loop that impinges on ERMD domains.

The discovery of ERMD has revealed a pivotal regulatory hub in the cell. The mitochondrial dynamics components DRP1 and Mff, and MFN2, which helps mediate mitochondrial-ER contacts important for Ca2+ homeostasis (17), do not play essential roles in the biogenesis of ERMD domains (13). Thus, the structural components essential for their formation are unknown. However, the assembly, organization, and number of ERMD domains in a given cell are likely to be dynamic and thus could also dictate the progression of apoptosis. It is possible that ERMD domains extend beyond the ER and mitochondrial outer membranes into the ER lumen and inner mitochondrial compartments, respectively, thereby integrating the functional status of both organelles. This is suggested by the regulation of mitochondrial outer membrane permeabilization by ER stress–induced apoptosis. Indeed, ER stress and mitochondrial dysfunction have been implicated in a shared set of diseases, such as neurodegeneration, which are associated with altered mitochondrial dynamics. This raises the intriguing possibility that alterations of ER-mitochondrial contacts may not only contribute to the normal regulation of cellular processes such as mitochondrial division and apoptosis, but may also be a contributory factor in disease (18).

References and Notes

  1. Acknowledgments: J.N. and S.H. are supported by the NIH (R01GM062942, R01GM097432, and K99HL103722).

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