Mitochondrial functions during cell death, a complex (I–V) dilemma

During apoptosis in vertebrate cells, the process of mitochondrial outer membrane permeabilization (MOMP) appears to represent a point-of-no-return for many cell types (for a review, see Von Ahsen et al.¹ and Waterhouse et al.²). Several mechanisms for cytochrome c release have been proposed including disruption of the outer membrane, opening of the permeability transition pore and formation of pores for cytochrome c release (for a review see Von Ahsen et al.¹). Recently Kuwana et al.³ presented results strongly suggesting that MOMP requires neither the mitochondrial matrix, the inner membrane, nor mitochondrial proteins other than proapoptotic members of the Bcl-2 family. In this study, using a stepwise reductionist approach, we demonstrated that Bax, activated by Bid or by peptides corresponding to BH3 domains, was able to produce membrane openings sufficient to release high molecular weight dextrans. This permeabilization event was observed in mitochondria (to release cytochrome c), vesicles composed of purified mitochondrial outer membranes, vesicles composed of mitochondrial lipids, and vesicles composed of synthetic lipids, and in each case similar concentrations of Bax were effective. This required the mitochondrial lipid cardiolipin, and was inhibited by anti-apoptotic Bcl-x_L. These results suggest that the proapoptotic ‘multidomain’ members of the Bcl-2 family, such as Bax, are sufficient to produce MOMP. However, Scorrano et al.⁴ suggested that most of the cytochrome c is sequestered in mitochondrial cristae and that the ‘BH3-only’ molecule tBID induces a striking remodeling of mitochondrial structure with mobilization of the cytochrome c stores (approximately 85%) in cristae. This remodeling appeared to require a mitochondrial permeability transition. Nevertheless, time-lapsed video microscopy and rapid filtration techniques have failed to provide evidence of a two-compartment model for cytochrome c release in intact cells.^5,6 In particular, in these studies, the rate of release of cytochrome c-GFP from mitochondria during apoptosis was observed to be temperature independent, suggesting that temperature-sensitive permeability transition and remodeling events do not play a prominent role in cytochrome c release, at least in the cells that were investigated.

With the exception of neurons,⁷ most cells that release the proteins of the mitochondrial intermembrane space during apoptosis appear to be committed to die whether or not caspases are activated. In the presence of caspase inhibitors⁸ or in cells lacking Apaf-1,⁹ MOMP seems to be lethal, and although the cells die via a process that does not closely resemble apoptosis, antiapoptotic proteins such as Bcl-2, which block MOMP, also block the cell death.¹⁰

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