Multiple entanglements of different cell death pathways, in which caspase-8 and BID interact with cardiolipin*, have been identified

Mitochondria play a central role in cellular bioenergetics, being major counterparts in ATP production 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, activation of the mitochondrial pathway is required for the induction of apoptosis in cells (extrinsic pathway), referred to as "type II" cells. In type I cells, activation of the extrinsic pathway through a large amount of caspase-8 allows direct activation of caspase-3 and is sufficient to induce apoptosis. This small review is dedicated to the often forgoten molecule of the BCL-2 family, BID. Special emphasis will be placed on the importance of the cardiolipin/caspase-8/BID platform located at the outer mitochondrial membrane surface that generates tBID, which is the actor of BAX/BAK delocalization and oligomerization at the mitochondrial surface and then transmits death signals in the apoptotic pathway. New insights into the regulation of caspase-8 and BID have emerged, and their originality in the context of their activation and function will be highlighted. We will focus on results from biophysical studies of artificial membranes, i.e., lipid-supported monolayers or giant unilamellar vesicles containing cardiolipin. The destabilization of mitochondrial bioenergetics by tBID insertion at the mitochondrial contact site is presented. Since it inhibits the electron transfer chain, superoxide anion generation is essential for BAX oligomerization. We will take you on a journey through these new developments that reveal a surprisingly high degree of redundancy and crosstalk between the apoptotic, necroptotic, and pyroptotic cell death pathways. Taken together, the mitochondrial contact site and cristae organization system (MICOS) is a critical determinant of mitochondrial membrane architecture and physiology. Its close crosstalk with many other mitochondrial protein machineries identifies the MICOS as a central hub in an interwoven network that ensures mitochondrial functionality and integration into the cellular context. It is becoming increasingly clear that the activation platform built around caspase-8/cardiolipin and BID is involved in multiple types of cell death, including apoptosis, ferroptosis (oxytosis), necroptosis and autophagic death.