The role of cardiolipin in promoting the membrane pore-forming activity of BAX oligomers

Abstract

BCL-2-associated X (BAX) protein acts as a gatekeeper in regulating mitochondria-dependent apoptosis. Under cellular stress, BAX becomes activated and transforms into a lethal oligomer that causes mitochondrial outer membrane permeabilization (MOMP). Previous studies have identified several structural features of the membrane-associated BAX oligomer; they include the formation of the BH3-in-groove dimer, the collapse of the helical hairpin α5-α6, and the membrane insertion of α9 helix. However, it remains unclear as to the role of lipid environment in determining the conformation and the pore-forming activity of the BAX oligomers. Here we study molecular details of the membrane-associated BAX in various lipid environments using fluorescence and ESR techniques. We identify the inactive versus active forms of membrane-associated BAX, only the latter of which can induce stable and large membrane pores that are sufficient in size to pass apoptogenic factors. We reveal that the presence of CL is crucial to promoting the association between BAX dimers, hence the active oligomers. Without the presence of CL, BAX dimers assemble into an inactive oligomer that lacks the ability to form stable pores in the membrane. This study suggests an important role of CL in determining the formation of active BAX oligomers.

Regulation of Mammalian Mitochondrial Dynamics: Opportunities and Challenges

“…In addition, mitochondrial membrane phospholipids have been suggested to play a role in the regulation of apoptosis (194), and accumulating evidence suggests that CL acts as an interaction platform to recruit apoptotic factors such as tBid and Bax (195)(196)(197)(198). CL is also essential for promoting the association between BAX dimers, hence CL plays an important role in controlling the formation of active BAX oligomers (199). Ceramide and sphingolipid are also reported to be critical for the formation of Bax oligomers during apoptosis (200,201).…”

Mitochondria as intracellular signaling platforms in health and disease

“…In mitochondrial-dependent apoptosis, the recruitment and activation of the apoptotic initiator protease caspase-8, its substrate BH3-interacting domain death agonist (BID), and the downstream effector BCL-2–associated X (BAX) are all dependent on the presence of cardiolipin in the OMM ( Gonzalvez et al, 2008 ; Kuwana et al, 2002 ; Lutter et al, 2000 ). The interactions among truncated BID (tBID), BAX, and cardiolipin drive the formation of supramolecular complexes containing BAX oligomers on the OMM surface that mediate membrane permeabilization and cytochrome c release ( Kuwana et al, 2002 ; Lai et al, 2019 ; Lutter et al, 2000 ). The oxidation of cardiolipin reduces its interaction with cytochrome c, which further accelerates cytochrome c release to initiate apoptosis.…”

Mitochondria, OxPhos, and neurodegeneration: cells are not just running out of gas

“…Unsurprisingly, alterations in the concentration and/or transacylation of cardiolipin are associated with mitochondrial OxPhos defects (194) and with specific mitochondrial disorders, such as Barth syndrome (195,196). Cardiolipin could also influence bioenergetics indirectly, including regulation of the orientation of the ADP/ATP carrier in the IMM (197) via modulation of mitochondrial creatine kinase activity (198), or even via regulation of BAX oligomeric pores on mitochondrial outer membrane (199).…”