Caspase-independent Mitochondrial Cell Death Results from Loss of Respiration, Not Cytotoxic Protein Release

Lartigue, Lydia; Kushnareva, Yulia; Seong, Youngmo; Lin, Helen; Faustin, Benjamin; Newmeyer, Donald D.

doi:10.1091/mbc.e09-07-0649

Cited by 111 publications

(88 citation statements)

References 89 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In agreement with this model, following mitochondrial permeabilisation, there is a rapid loss in the activity of respiratory complexes I and IV (Lartigue et al, 2009). Exactly why these complexes lose function is unclear but it might be due to degradation of one or several subunits of these multi-protein complexes.…”

Section: Executing or Evading Cicdsupporting

confidence: 59%

Die another way – non-apoptotic mechanisms of cell death

Tait

Ichim

Green

2014

Journal of Cell Science

315

246

View full text Add to dashboard Cite

Regulated, programmed cell death is crucial for all multicellular organisms. Cell death is essential in many processes, including tissue sculpting during embryogenesis, development of the immune system and destruction of damaged cells. The best-studied form of programmed cell death is apoptosis, a process that requires activation of caspase proteases. Recently it has been appreciated that various non-apoptotic forms of cell death also exist, such as necroptosis and pyroptosis. These non-apoptotic cell death modalities can be either triggered independently of apoptosis or are engaged should apoptosis fail to execute. In this Commentary, we discuss several regulated non-apoptotic forms of cell death including necroptosis, autophagic cell death, pyroptosis and caspase-independent cell death. We outline what we know about their mechanism, potential roles in vivo and define outstanding questions. Finally, we review data arguing that the means by which a cell dies actually matters, focusing our discussion on inflammatory aspects of cell death.

show abstract

Section: Executing or Evading Cicdsupporting

confidence: 59%

Die another way – non-apoptotic mechanisms of cell death

Tait

Ichim

Green

2014

Journal of Cell Science

315

246

View full text Add to dashboard Cite

show abstract

“…1). Provided MOMP has occurred, cells can also undergo caspase-independent cell death that is most likely to be a consequence of a progressive decline in mitochondrial function (Lartigue et al, 2009;Tait and Green, 2008). The absolute requirement for mitochondria in intrinsic apoptosis is best demonstrated by two findings: cells deficient in both BAX and BAK are resistant to all intrinsic apoptotic stimuli, and cells expressing a point mutant of cytochrome c (K72A), with a reduced ability to activate caspases but that retains respiratory-chain function, fail to efficiently activate caspases following MOMP, indicating that mitochondria, through MOMP, are required for caspase activation and apoptosis (Hao et al, 2005;Wei et al, 2001).…”

Section: Mitochondrial Outer Membrane Permeabilisation and Apoptosismentioning

confidence: 99%

Mitochondria and cell signalling

Tait

Green

2012

Journal of Cell Science

382

250

View full text Add to dashboard Cite

Commentary 807Introduction Mitochondria are often termed the 'powerhouse' of the cell for good reason. Not only do mitochondria have a key role in ATP synthesis, but they are also crucial for various other cellular processes, including fatty acid synthesis, Ca 2+ homeostasis and the biogenesis of haem and iron-sulphur proteins. Given this plethora of functions, it is perhaps not surprising that mitochondria are also heavily integrated into the cell signalling circuitry. The traditional view of mitochondria in signalling is that they represent signalling effectors, for example, by enabling the upregulation of ATP synthesis in response to growthpromoting stimuli. However, more recent evidence demonstrates that mitochondria also actively participate in numerous biological processes by acting as initiators and transducers of cell signalling. In general, mitochondria regulate cell signalling through two means: serving as physical platforms on which protein-protein signalling interactions occur, and by regulating the levels of intracellular signalling molecules, including Ca 2+ and reactive oxygen species (ROS). Consequently, mitochondria have been implicated in the regulation of various processes, including growth factor signalling, differentiation and hypoxic stress responses, which are discussed elsewhere (Antico Arciuch et al., 2012;Chandel, 2010;Finkel, 2011;Gunter et al., 2004). In this Commentary, we focus on the signalling roles that mitochondria have in cell death, innate immunity and autophagy. These areas are collectively discussed because of their numerous interconnections. For example, cell death acts as a firstline defence against invading pathogens and serves to alert the innate immune system to infection, whereas autophagy generally acts as a pro-survival mechanism and controls innate immunity at multiple levels, such as through the regulation of pro-inflammatory cytokine production. Mitochondrial regulation of cell death signallingProgrammed cell death is required for proper development and tissue homeostasis in all multicellular organisms, and its deregulation contributes to various diseases including cancer and neurodegeneration. The predominant form of programmed cell death is apoptosis, a process that requires activation of the caspase proteases. Once activated, caspases cleave several hundred different proteins, leading to rapid apoptotic cell death (Taylor et al., 2008). This is associated with characteristic morphological changes, including plasma membrane blebbing and nuclear condensation. Mitochondria are involved in regulating caspase activity and apoptosis in all multicellular organisms to varying degrees and through different mechanisms (Oberst et al., 2008). For example, in the nematode Caenorhabditis elegans, mitochondria serve a non-essential role during apoptosis because, even though they act as a platform for key apoptotic signalling proteins, these proteins do not have to be localised to mitochondria per se in order to regulate apoptosis (Tan et al., 2007). In other organisms, mitoch...

show abstract

“…This means that cells can recover from MOMP only under exceptional circumstances. [22][23][24] Even in cases where apoptosis is initiated by ligation of death receptors, through the extrinsic pathway, the upstream signals often require amplification by the mitochondrial pathway. Thus, MOMP is frequently the decisive event preceding cell death.…”

Section: Apoptosis and Bcl-2 Family Proteinsmentioning

confidence: 99%

The rheostat in the membrane: BCL-2 family proteins and apoptosis

et al. 2013

View full text Add to dashboard Cite

Apoptosis, a mechanism for programmed cell death, has key roles in human health and disease. Many signals for cellular life and death are regulated by the BCL-2 family proteins and converge at mitochondria, where cell fate is ultimately decided. The BCL-2 family includes both pro-life (e.g. BCL-XL) and pro-death (e.g. BAX, BAK) proteins. Previously, it was thought that a balance between these opposing proteins, like a simple 'rheostat', could control the sensitivity of cells to apoptotic stresses. Later, this rheostat concept had to be extended, when it became clear that BCL-2 family proteins regulate each other through a complex network of bimolecular interactions, some transient and some relatively stable. Now, studies have shown that the apoptotic circuitry is even more sophisticated, in that BCL-2 family interactions are spatially dynamic, even in nonapoptotic cells. For example, BAX and BCL-XL can shuttle between the cytoplasm and the mitochondrial outer membrane (MOM). Upstream signaling pathways can regulate the cytoplasmic-MOM equilibrium of BAX and thereby adjust the sensitivity of cells to apoptotic stimuli. Thus, we can view the MOM as the central locale of a dynamic life-death rheostat. BAX invariably forms extensive homo-oligomers after activation in membranes. However, recent studies, showing that activated BAX monomers determine the kinetics of MOM permeabilization (MOMP), perturb the lipid bilayer and form nanometer size pores, pose questions about the role of the oligomerization. Other lingering questions concern the molecular mechanisms of BAX redistribution between MOM and cytoplasm and the details of BAX/BAK-membrane assemblies. Future studies need to delineate how BCL-2 family proteins regulate MOMP, in concert with auxiliary MOM proteins, in a dynamic membrane environment. Technologies aimed at elucidating the structure and function of the full-length proteins in membranes are needed to illuminate some of these critical issues.

show abstract

Caspase-independent Mitochondrial Cell Death Results from Loss of Respiration, Not Cytotoxic Protein Release

Cited by 111 publications

References 89 publications

Die another way – non-apoptotic mechanisms of cell death

Die another way – non-apoptotic mechanisms of cell death

Mitochondria and cell signalling

The rheostat in the membrane: BCL-2 family proteins and apoptosis

Contact Info

Product

Resources

About