A mechanistic view of mitochondrial death decision pores

Abstract

Mitochondria increase their outer and inner membrane permeability to solutes, protons and metabolites in response to a variety of extrinsic and intrinsic signaling events. The maintenance of cellular and intraorganelle ionic homeostasis, particularly for Ca 2+ , can determine cell survival or death. Mitochondrial death decision is centered on two processes: inner membrane permeabilization, such as that promoted by the mitochondrial permeability transition pore, formed across inner membranes when Ca 2+ reaches a critical threshold, and mitochondrial outer membrane permeabilization, in which the pro-apoptotic proteins BID, BAX, and BAK play active roles. Membrane permeabilization leads to the release of apoptogenic proteins: cytochrome c, apoptosisinducing factor, Smac/Diablo, HtrA2/Omi, and endonuclease G. Cytochrome c initiates the proteolytic activation of caspases, which in turn cleave hundreds of proteins to produce the morphological and biochemical changes of apoptosis. Voltage-dependent anion channel, cyclophilin D, adenine nucleotide translocase, and the pro-apoptotic proteins BID, BAX, and BAK may be part of the molecular composition of membrane pores leading to mitochondrial permeabilization, but this remains a central question to be resolved. Other transporting pores and channels, including the ceramide channel, the mitochondrial apoptosis-induced channel, as well as a non-specific outer membrane rupture may also be potential release pathways for these apoptogenic factors. In this review, we discuss the mechanistic models by which reactive oxygen species and caspases, via structural and conformational changes of membrane lipids and proteins, promote conditions for inner/outer membrane permeabilization, which may be followed by either opening of pores or a rupture of the outer mitochondrial membrane. Correspondence

Apoptosis: Reprogramming and the Fate of Mature Cells

“…The intrinsic pathway, which is also known as mitochondria-mediated death pathway, is initiated by damage to mitochondria which results in the release of a series of proteins into cytoplasm, including cytochrome c. When released into the cytoplasm, cytochrome c complexes with Apaf-1, and this complex further activates caspase-9 and ultimately caspase-3. Activated caspase-3 further cleaves critical intracellular proteins and thereby induces the final stage of cell death [4][5][6].…”

“…A critical event for the intrinsic pathway is release of cytochrome c from mitochondria, a step strictly regulated by members of the B-cell lymphoma 2 (Bcl-2) family [6,7]. Members of this family are divided into two subfamilies: one includes the proapoptotic proteins such as Bak, Bax, and Bid; another includes the antiapoptotic proteins such as Bcl-2 and Bcl-xL [5].…”

NSP 5a3a: A Potential Novel Cancer Target in Head and Neck Carcinoma

“…and Bim can activate pro-apoptotic members Bax/Bak [7][8]. This activation of Bax and Bak leads to the cellular commitment stage in apoptosis by which there is an organelle dysfunction of the mitochondria and endoplasmic reticulum characterized along with a change in organelle homeostasis involving calcium levels in turn promoting the release of apoptogenic factors from mitochondria [7][8].…”

“…This activation of Bax and Bak leads to the cellular commitment stage in apoptosis by which there is an organelle dysfunction of the mitochondria and endoplasmic reticulum characterized along with a change in organelle homeostasis involving calcium levels in turn promoting the release of apoptogenic factors from mitochondria [7][8]. The release of apoptogenic factors such as: of Cytochrome C, SMAC/Diablo, Omi/HtrA2, and AIF (Apoptosis inducing factor) in turn mark the execution stage in which activate further downstream pathways leading to the common end result of cell death [7][8]. Cytochrome C will form a molecular complex with Apaf-1 and caspase 9 leading to formation of an Apoptosome that in turn can activate down-stream effectors such as caspase 3,6, and 7 [7][8].…”

“…The release of apoptogenic factors such as: of Cytochrome C, SMAC/Diablo, Omi/HtrA2, and AIF (Apoptosis inducing factor) in turn mark the execution stage in which activate further downstream pathways leading to the common end result of cell death [7][8]. Cytochrome C will form a molecular complex with Apaf-1 and caspase 9 leading to formation of an Apoptosome that in turn can activate down-stream effectors such as caspase 3,6, and 7 [7][8]. SMAC/Diablo along with Omi/ HtrA2 can bind to IAPs (inhibitors of apoptosis proteins), such as XIAP and cIAP1, disabling them from inhibiting caspase activation.…”