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. 2014 Oct;5(10):737-49.
doi: 10.1007/s13238-014-0089-1. Epub 2014 Jul 31.

Mitochondria-mediated apoptosis in mammals

Shunbin Xiong  1 , Tianyang Mu, Guowen Wang, Xuejun Jiang
Affiliations

Mitochondria-mediated apoptosis in mammals

Shunbin Xiong et al. Protein Cell. 2014 Oct.

Abstract

The mitochondria-mediated caspase activation pathway is a major apoptotic pathway characterized by mitochondrial outer membrane permeabilization (MOMP) and subsequent release of cytochrome c into the cytoplasm to activate caspases. MOMP is regulated by the Bcl-2 family of proteins. This pathway plays important roles not only in normal development, maintenance of tissue homeostasis and the regulation of immune system, but also in human diseases such as immune disorders, neurodegeneration and cancer. In the past decades the molecular basis of this pathway and the regulatory mechanism have been comprehensively studied, yet a great deal of new evidence indicates that cytochrome c release from mitochondria does not always lead to irreversible cell death, and that caspase activation can also have non-death functions. Thus, many unsolved questions and new challenges are still remaining. Furthermore, the dysfunction of this pathway involved in cancer development is obvious, and targeting the pathway as a therapeutic strategy has been extensively explored, but the efficacy of the targeted therapies is still under development. In this review we will discuss the mitochondria-mediated apoptosis pathway and its physiological roles and therapeutic implications.

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Figures

Figure 1
Figure 1
Schemes showing three groups of Bcl2- family proteins. BH: Bcl-homology domain; TM: transmembrane domains
Figure 2
Figure 2
An overview of the mitochondria-mediated caspase activation pathway. Upon apoptotic stimuli such as DNA damage, growth factor deprivation, etc. BAX/BAK form oligomeric complexes to mediate cytochrome c release from the mitochondria to the cytosol. The released cytochrome c forms the apoptosome with Apaf-1 and subsequently activates the initiator caspase, caspase-9, which cleaves and activates effector caspases, caspase-3 and caspase-7, leading to ultimate apoptotic cell death. Other proapoptotic proteins including Smac, Omi, and ARTS also function to repress IAPs to enhance apoptosis. WD40: WD40 repeat domain; CARD: a caspase recruitment domain
Figure 3
Figure 3
The structure of IAP family proteins. The IAP family protein has at least one baculovirus inhibitor of apoptosis protein repeat (BIR) domain. Several IAPs also contain a RING-zinc finger domain at the carboxy terminus with autoubiquitination and degradation activity. c-IAP1 and c-IAP2 have a caspase recruitment domain (CARD) between the BIR domains and the RING domain. BRUCE contains an ubiquitin-conjugation domain (UBC)
Figure 4
Figure 4
The therapeutic agents developed to target the mitochondrial apoptotic pathway. Oblimersen sodium is a Bcl-2 antisense oligonucleotide compound. BH3 mimetic compounds include ABT- 737, ABT-263, and JY-1-106. Nutlin and MI-219 block Mdm2 and p53 interaction to activate p53 transcription activity to induce the expression of Puma and Bax. Smac mimetics and the antisense oligonucleotide AEG35156 are inhibitors of XIAP. 4-Pyridineethanol (PETCM), gambonic acid, and the gambonic acid derivative MX-206 can activate caspases-3
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