Bax and Bak function as the outer membrane component of the mitochondrial permeability pore in regulating necrotic cell death in mice.

In all multicellular plants and animals, cells are continuously dying and being replaced. There are a number of different types of cell death, but two of the best studied are apoptosis and necrosis. Apoptosis, sometimes referred to as ‘cell suicide’, is a form of programmed cell death that is generally beneficial to the organism. Necrosis, however, occurs whenever cells are damaged—for example, due to a lack of oxygen—and can trigger harmful inflammation in surrounding tissue. Although the processes leading up to apoptosis and necrosis are very different, they both involve regulated changes in mitochondria—the organelles that supply cells with chemical energy. Mitochondria have a distinctive appearance, being enclosed by two membranes, the innermost of which is highly folded. During apoptosis, large pores form in the outer membranes of mitochondria. These pores are generated by two proteins—Bax and Bak—and they enable the mitochondrion to release proteins that activate processes involved in apoptosis. Pores also form in the mitochondrial membrane during necrosis. However, these mitochondrial permeability transition pores (MPTPs) occur simultaneously in both the inner and outer membranes and are thought to lead to swelling and rupture of mitochondria. Now, Karch et al. have shown that Bax and Bak are also involved in the formation of these permeability pores that underlie necrosis. When mouse cells that had been genetically modified to lack Bak and Bax were grown in cell culture, they were found to be resistant to substances that normally induce necrosis. Instead, their mitochondria continued to function normally, suggesting that MPTPs cannot form in the absence of Bak and Bax. Karch et al. then generated mice with heart cells that lack Bax and Bak, and deprived their hearts of oxygen to simulate a heart attack. Compared to normal mice, the genetically modified animals experienced less damage to their heart muscle, suggesting that the absence of Bax and Bak prevents cell death due to necrosis. If Bax and Bak are involved in both apoptosis and necrosis, inhibiting them could be a powerful therapeutic approach for preventing all forms of cell death during heart attacks or in certain degenerative diseases.