BAX and BAK: Mitochondrial Gatekeepers of Apoptosis

The BCL-2 Family in Three Groups

The family divides into effectors (BAX, BAK, and the less-studied BOK), anti-apoptotic guardians (BCL2, BCL-XL, MCL1, BCL-W, BFL-1), and BH3-only proteins that sense stress.

BH3-only proteins come in two flavours: activators (BIM, BID, PUMA) that can switch on BAX and BAK directly, and sensitisers (BAD, NOXA, others) that work by occupying the guardians.

Activating BAX and BAK

In healthy cells BAX shuttles between the cytosol and the mitochondrial surface, while BAK sits on the membrane held inactive. Activator BH3-only proteins trigger a conformational change that exposes their own BH3 domains.

Activated monomers then dimerise and assemble into larger oligomers, which is the point of no return for the intrinsic pathway.

Breaching the Membrane

BAX/BAK oligomers form large proteolipid pores, or macropores, in the outer mitochondrial membrane. These release cytochrome c and SMAC/DIABLO, and can be large enough for inner-membrane contents, including mitochondrial DNA, to herniate outward.

Released mitochondrial DNA can engage the cGAS-STING pathway, linking apoptosis to innate-immune signalling, which is one reason the mode of cell death matters for anti-tumour immunity.

How the Guardians Hold the Line

BCL2, BCL-XL and MCL1 bind and neutralise both activator BH3-only proteins and activated BAX/BAK. A cell that is loaded with activator proteins but keeps them all bound is described as primed for death.

Primed cancer cells are highly sensitive to anything that displaces those interactions, which is the basis of BH3 mimetic drugs and of BH3 profiling as a laboratory assay.

BAX/BAK in Cancer

Outright BAX or BAK loss is relatively uncommon in solid tumours, though BAX frameshift mutations occur in mismatch-repair-deficient cancers. More often, tumours tilt the balance by overexpressing guardians.

Acquired BAX mutations have been reported as a resistance mechanism to BH3 mimetics, illustrating that the effector step remains essential for these drugs to work.

Key Takeaways

• ·BAX and BAK execute mitochondrial permeabilisation, the commitment step of intrinsic apoptosis.
• ·Activator BH3-only proteins switch them on; anti-apoptotic proteins hold them off.
• ·BAX/BAK macropores can release mitochondrial DNA and engage innate immunity.
• ·Most cancers block this step by raising guardian proteins rather than deleting BAX/BAK.