Caspase-8/CL/BID pla/orm 1 Multiple entanglements of different cell death pathways, in which caspase-8 and BID interact with cardiolipin*, have been identified

Patrice X. PETIT^*

• Centre National de la Recherche Scientifique (CNRS), Paris, France

Mitochondria play a central role in cellular bioenerge?cs, being major counterparts in ATP produc?on and thus in the maintenance of cells, but they are also key mediators of different types of cell death (apoptosis, necroptosis, ferroptosis, etc.) and are among the main players in autophagy. With respect to death receptor-mediated apoptosis, ac?va?on of the mitochondrial pathway is required for the induc?on of apoptosis in cells (extrinsic pathway), referred to as "type II" cells. In type I cells, ac?va?on of the extrinsic pathway through a large amount of caspase-8 allows direct ac?va?on of caspase-3 and is sufficient to induce apoptosis. This small review is dedicated to the oSen forgoten molecule of the BCL-2 family, BID. Special emphasis will be placed on the importance of the cardiolipin/caspase-8/BID pla/orm located at the outer mitochondrial membrane surface that generates tBID, which is the actor of BAX/BAK delocaliza?on and oligomeriza?on at the mitochondrial surface and then transmits death signals in the apopto?c pathway. New insights into the regula?on of caspase-8 and BID have emerged, and their originality in the context of their ac?va?on and func?on will be highlighted. We will focus on results from biophysical studies of ar?ficial membranes, i.e., lipid-supported monolayers or giant unilamellar vesicles containing cardiolipin. The destabiliza?on of mitochondrial bioenerge?cs by tBID inser?on at the mitochondrial contact site is presented. Since it inhibits the electron transfer chain, superoxide anion genera?on is essen?al for BAX oligomeriza?on. We will take you on a journey through these new developments that reveal a surprisingly high degree of redundancy and crosstalk between the apopto?c, necropto?c, and pyropto?c cell death pathways. Taken together, the mitochondrial contact site and cristae organiza?on system (MICOS) is a cri?cal determinant of mitochondrial membrane architecture and physiology. Its close crosstalk with many other mitochondrial protein machineries iden?fies the MICOS as a central hub in an interwoven network that ensures mitochondrial func?onality and integra?on into the cellular context. It is becoming increasingly clear that the ac?va?on pla/orm built around caspase-8/cardiolipin and BID is involved in mul?ple types of cell death, including apoptosis, ferroptosis (oxytosis), necroptosis and autophagic death.