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Apoptosis and Mitochondria

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Signaling Pathways in Liver Diseases

Abstract

Among the various recognized forms of cell death that include necrosis and autophagy, apoptosis or programmed cell death is evolutionarily conserved, highly organized, and characterized by unique nuclear changes, chromatin shrinkage, DNA fragmentation, membrane blebbing, and formation of apoptotic bodies that contain components of the dying cell. Apoptosis is a crucial component of life that eliminates unwanted cells and is vital for embryonic development, homeostasis, and immune defense. Dysregulation of apoptosis underlies many pathophysiological states and diseases. The key mediators of apoptotic cell death are cysteine proteases, called caspases, that work in a coordinated cascade to cleave key substrates and dismantle the cell [1]. The caspase cascade involves “initiator” caspases and “executioner” caspases that can be activated in different ways by different apoptotic stimuli. While changes in nuclei are characteristic in apoptotic cell death, other subcellular organelles are also involved such as endoplasmic reticulum, lysosomes, and, particularly, mitochondria. Moreover, although caspases are crucial in apoptosis, similar morphologic changes can be produced in a caspase-independent fashion. In vertebrates, caspase-dependent apoptosis occurs through two main pathways, the extrinsic pathway and the intrinsic pathway (Fig. 29.1). The extrinsic pathway is initiated upon the binding of an extracellular ligand to transmembrane death receptors of the TNF superfamily (see below), which leads to the assembly of the death-inducing signaling complex (DISC). The DISC then activates an initiator caspase, which triggers the enzymatic cascade that leads to apoptotic death. The intrinsic pathway, also known as the mitochondrial pathway, is activated by stimuli that lead to the permeabilization of the outer mitochondrial membrane (OMM) and the subsequent release of proteins from the mitochondrial intermembrane space (IMS), which initiate or regulate caspase activation, such as cytochrome c. Cytochrome c normally resides within the cristae of the inner mitochondrial membrane (IMM) and is effectively sequestered by narrow cristae junctions. Within the IMM, cytochrome c participates in the mitochondrial electron-transport chain, using its heme group as a redox intermediate to shuttle electrons between complex III and complex IV. However, when the cell detects an apoptotic stimulus, such as DNA damage, or metabolic stress, the intrinsic apoptotic pathway is triggered and mitochondrial cytochrome c is released into the cytosol. This process is thought to occur in two phases, first the mobilization of cytochrome c and then its translocation through permeabilized OMM. In addition to cytochrome c, other IMS proteins are mobilized and released into the cytosol where they are engaged in a strategic battle to promote or counteract caspase activation and hence cell death.

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Acknowledgments

This work was supported in part by the Research Center for Liver and Pancreatic Diseases Grant P50 AA 11999 funded by the US National Institute on Alcohol Abuse and Alcoholism, Plan Nacional de I + D Grants: SAF2005-03923, SAF2005-03943, SAF2006-06780, and FIS06/0395 and by the Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas (CIBEREHD) supported by the Instituto de Salud Carlos III.

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  1. Liver Unit and Centro de Investigaciones Biomédicas Esther Koplowitz, IMDiM, Hospital Clínic i Provincial and CIBEREHD, IDIBAPS, C/Villarroel 170, 08036, Barcelona, Spain

    Jose C. Fernández-Checa & Carmen Garcia-Ruiz

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  1. Jose C. Fernández-Checa
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  2. Carmen Garcia-Ruiz
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Correspondence to Jose C. Fernández-Checa .

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Editors and Affiliations

  1. Inselspital, Universität Bern, Murtenstr. 35, Bern, 3010, Switzerland

    Jean-Francois Dufour

  2. Klinik für Viszeral- und, Universitätsspital Zürich, Rämistr. 100, Zürich, 8091, Switzerland

    Pierre-Alain Clavien

Selected Reading

Selected Reading

102.Liu X, Kim CN, Yang J, Jemmerson R, Wang X (1996) Induction of apoptotic program in cell-free extracts: requirement for dATP and cytochrome c. Cell 86: 147–157. (This study is hallmark in the field of cell death regulation as it described for the first time the identification of cytochrome c released from mitochondria as a trigger for caspase activation, thereby hinting at the existence of the mitochondrial pathway of apoptosis.)

103.Kuwana T et al. (2002) Bid, Bax, and lipids cooperate to form supramolecular openings in the outer mitochondrial membrane. Cell 111: 331–342. (This study showed that Bax permeabilizes lipid membranes sufficiently to allow large molecules to pass through, and that this effect requires an activation signal that is provided by Bid. It also showed that specific lipids, such as cardiolipin, are implicated in the function of Bax.)

104.Schneider-Brachert, W. et al. (2004) Compartmen­talization of TNF receptor 1 signaling: internalized TNF receptosomes as death signaling vesicles. Immunity 21: 415–428. (This study highlights the relevance of TNFR1 internalization to recruit and activate downstream intermediates that signal cell death in endosomes and provides the mechanisms whereby TNFR1 activates SMases in acidic com­partments.)

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Fernández-Checa, J.C., Garcia-Ruiz, C. (2010). Apoptosis and Mitochondria. In: Dufour, JF., Clavien, PA. (eds) Signaling Pathways in Liver Diseases. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-00150-5_29

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