The expanding role of mitochondria in apoptosis
Apoptosis is then initiated by the release of mitochondrial pro-apoptotic proteins into the cytosol. association of Bcl-2 and Bcl-xL with Bax or BHonly. The role of mitochondria in apoptosis in three model systems. The membrane association of RHG proteins has been shown to be required for RHG-mediated. Mar 5, In this review, we discuss the role of apoptosis in the development and treatment of cancer. Specifically, we focus upon the mitochondrial.
But in any case, just painting broad strokes, we generally classify apoptosis as more of a controlled type of cell death. Whereas necrosis is more of an uncontrolled type of cell death, that usually is in response to extreme stress. Like in an extreme infection, or extreme trauma.
Apoptosis on the other hand, as its definition kind of implies here, it's a programmed type of cell death, has usually some big purpose. And often can confer some advantage to the organism. And one example of this is actually in embryological development, and specifically the development of our fingers and our toes. So let's take for example, the development of our hands. So early on in our development, when we're still a fetus, our hand looks something like a paw.
And through apoptosis, the tissue between our digits eventually dies off, and that purposeful, controlled death of this tissue ultimately allows us to produce a hand with five separated digits that we call fingers.
And with that in mind, we can actually brainstorm some other advantageous reasons that a cell might want to undergo cell death. So here I've kind of drawn a cell, and because I mentioned earlier the mitochondria plays a big role in apoptosis, I'm gonna go ahead and draw kind of a massive mitochondria in here.
Remember that the mitochondria has two membranes, I've drawn the outer membrane. And here I'm drawing the infoldings, or the cristae of the inner mitochondrial membrane. Now we just talked about one type of signal that induced a cell to undergo apoptosis, and that was a signal that was given during our embryological development.
But there are also other things that can induce our cell to undergo apoptosis as well. And I want to touch on several of these factors right now. First off, turns out that DNA damage can induce cell death. And I should mention that our cells have repair mechanisms in place that can deal with DNA damage, but in some cases the DNA damage might be quite extensive or our repair mechanisms are simply not equipped to repair DNA damage from some reason or another, and so the kind of last, fail-safe mechanism to deal with this, is to induce programmed cell death.
Mitochondrial apoptosis-induced channel - Wikipedia
And of course, this is advantageous for our organism, because we wouldn't want a cell with damaged DNA to pass that damaged DNA down to its offspring cell. So this is a way that we can essentially get rid of those damaged cells. In addition, infection, especially by viruses, because viruses like to hang out inside of our cells, can also induce programmed cell death.
And in this case, often times it's immune cells, that remember, are kind of our army against infection that see that there are specific proteins on cells that have been infected by viruses.
Mitochondrial Dynamics: Functional Link with Apoptosis
The cytosolic region of the ER integral membrane protein Bap31 is cleaved by activated caspase-8 to generate proapoptotic p20Bap31, which causes rapid transmission of ER calcium signals to the mitochondria via the IP3 receptor. The massive influx of calcium leads to mitochondrial fission, cristae remodeling, and cytochrome release. Mfn2 is enriched in the mitochondria-associated membranes MAM of the endoplasmic reticulum ERwhere it interacts with Mfn1 and Mfn2 on the mitochondria to form interorganellar bridges.
MICU1, mitochondrial calcium uptake 1. A pharmacologic inhibitor of Drp1-GTPase, mdivi-1, inhibits tBid-dependent cytochrome release from isolated mitochondria that are incapable of undergoing fission in vitro.
These findings suggest either that mdivi-1 inhibits other Drp1 functions than mediating mitochondrial fission or that it inhibits molecules other than Drp1 that regulate cytochrome release [ 68 ]. Martinou and coworkers recently demonstrated that Drp1 promotes the formation of a nonbilayer hemifission intermediate in which the activated and oligomerized Bax forms a hole, leading to MOMP [ 69 ]. Therefore, although mitochondrial fragmentation is indeed associated with apoptosis, excessive mitochondrial fragmentation can occur in a variety of conditions independently of apoptosis processes, such as that occurring upon exposure to carbonyl cyanide m-chlorophenyl hydrazone CCCPuncoupling agents that disrupt the electrochemical potential of the MIM [ 70 ].
Thus, how Drp1 contributes to apoptosis is an important issue for future studies. Cristae Remodeling and Apoptosis Opa1, localizing in the inner membrane as a hetero-oligomeric complex of large and small size forms, regulates MIM fusion and is necessary for maintenance of the cristae junctions independently of mitochondrial fusion. The majority of cytochrome is confined within the cristae folds and the complete release and mobilization of cytochrome in the IMS require cristae remodeling or cristae-junction opening [ 71 ].
Opa1 depletion by RNAi leads to fragmented mitochondria with disrupted cristae structures and an increase in the sensitivity to the apoptotic stimuli [ 657273 ].
Further, during early apoptosis, the Opa1 hetero-oligomer is disrupted, the cristae widen, and cytochrome is released into the IMS. Of note, we demonstrated that Opa1 RNAi HeLa cells have disrupted cristae and efficient sensitivity to apoptosis, based on the cytochrome release. These results suggest that cristae disorganization and mitochondrial fission as well as MOMP State I in Figure 2 are essentially required for efficient cytochrome release and each can limit the initial apoptosis progression.
In contrast to these observations, detailed analysis with transmission electron microscopy and three-dimensional electron microscope tomography revealed that neither cristae reorganization nor cristae-junction opening is required for the complete release of cytochrome [ 74 ]. Thus, the requirement of Opa1-dependent cristae remodeling for cytochrome release remains to be reconciled.
Mitochondrial Morphologic Responses in Cell Survival Many lines of evidence indicate that the efficiency of oxidative phosphorylation by the mitochondrial electron transport chain is affected by the degree of mitochondrial connectivity; a highly connected mitochondrial network correlates with increased ATP production efficiency. Mitochondria hyperfuse and form a highly interconnected network when cells are exposed to modest levels of stress e.Mitochondria, Apoptosis, and Oxidative Stress
This seems to be a counterstress action of the cells that is necessary for survival by increased mitochondrial ATP production. Under nutrient starvation, mitochondrial fission is repressed in response to PKA-dependent Drp1 phosphorylation of Drp1 Ser due to increased cAMP levels Figure 1resulting in elongation of the mitochondria with a higher density of cristae and a capacity for efficient ATP production.
This response protects mitochondria from autophagosomal degradation and sustains cell viability [ 7677 ]. Alternatively, dysfunctional or damaged mitochondria are selectively eliminated by autophagic degradation termed mitophagy: As it is thought that mitochondrial fission is related to the progression of mitophagy, inhibition of mitochondrial fission by the dominant negative mutant of Drp1 or specific inhibitor of Drp1-GTPase mdivi-1 compromises Parkin-PINK1-dependent mitophagy [ 83 ].
Together, mitochondrial fusion and fission are more likely to be involved in mitochondrial quality control in healthy cells. A similar structure is expected to exist in mammalian cells; a mammalian homolog of yeast Gem1, MIRO, is detected in the proximity of the ER-mitochondria [ 90 ]. Interactions between the mitochondria and ER are also supported by the finding that the ER can elicit mitochondrial apoptosis.
Mammalian mitochondrial Fis1 is an ortholog of yeast Fis1 thought to be involved in recruitment of Drp1 to the mitochondria as in yeast [ 94 ]. Although recent experiments revealed that Fis1 is not necessary for Drp1-dependent mitochondrial fission in mammals [ 102425 ], it might have another important role.
- Mitochondrial apoptosis-induced channel
- Mitochondria, apoptosis, and oxidative stress
- The expanding role of mitochondria in apoptosis
Interestingly, Iwasawa et al. Apoptotic signals induce cleavage of Bap31 into p20Bap31, which causes the rapid transmission of ER calcium to the mitochondria through inositol triphosphate receptors at the ER-mitochondria junction [ 97 ]. Thus, the hFis1-Bap31 complex, bridging the mitochondria and ER, functions as a platform to activate the initiator procaspase in apoptosis signaling Figure 3. Distinct from the substrate or ion transfer function of the ER-mitochondria contact, Friedman et al.
At the contacts, the ER wraps around the mitochondria to form constrictions, where Drp1 and Mff accumulate and facilitate mitochondrial fission. Interestingly, ER-localized Mfn2 which was shown to be involved in tethering mitochondria and ER [ 91 ] is not involved in this reaction [ 99 ]. Conclusions Although key proteins regulating mammalian mitochondrial dynamics have been identified during the past decade, molecular mechanisms, their coordination, and physiologic functions in distinct tissues are poorly understood, especially in fission reaction: Furthermore, involvement of Fis1 in the regulation of mitochondrial dynamics and its physiologic function remain to be investigated.
The mechanisms coordinating these reactions and the effect of Bcl-2 family proteins on mitochondrial fission and fusion machineries remain to be analyzed at the molecular level.
Recent studies have revealed that the ER-mitochondria contacts MAM structures are involved in the regulation of mitochondrial energy, lipid metabolism, calcium signaling, and even in mitochondrial fission. Identification of additional structural components, regulation of assembly of these structures, and relation between various complexes will reveal novel aspects of cell physiology regulation through communication between mitochondria and ER.
The direct competition and mutual exclusion between Smac and activated caspases suggest an interesting feedback system in cells. When released from mitochondria, cytochrome c binds to Apaf-1 with high affinity and triggers apoptosome formation and caspase activation Purring et al.
However, in the presence of high levels of IAPs, this pathway will be aborted when IAPs bind and inhibit the active caspases in the apoptosome Bratton et al. The inhibition could become permanent because many IAPs also contain a RING finger domain that may target the bound caspases for proteasome degradation Yang et al.
Such a system provides a safety net for the transient or incidental mitochondria leakage of cytochrome c, a much smaller molecule than Smac Chai et al. If the damage to mitochondria is severe and persistent, more Smac will be released, together with cytochromec, to remove IAP inhibition and allow apoptosis to proceed. The regulation provided by the Smac and IAPs interaction may not be limited to the cytochrome c pathway Green ; Srinivasula et al.
However, because this pathway and the cytochrome c pathway converge at the step of caspase-3 activation, high levels of IAP molecules such as XIAP are able to abort the receptor pathway by inhibiting caspase For apoptosis to proceed, the receptor pathway may rely on the activation of Bid, a BH3-only protein that is activated by the initiator caspase in the receptor pathway, caspase-8 Li et al. Activated Bid induces the release of apoptogenic proteins including Smac from the mitochondria to counter XIAP inhibition.
The finding that Smac interacts with IAPs mainly through a few amino acid residues at the N terminus of Smac provides a plausible explanation for a puzzling observation in the field.
Despite similar biochemical activity, Reaper, Grim, and Hid share little sequence homology other than a few amino acids at their N termini; no mammalian homologs for any of those three proteins have been found. However, if the comparison is restricted to the N-terminal four amino acids of mature Smac and the few amino acid residues of Reaper, Grim, and Hid after their initiator methionines, obvious homology is noted Liu et al.
The presence of Smac does not explain why those knockout cells deficient in Apaf-1, cytochrome c, orcaspase-9 still die without apparent caspase activation. It is likely that other caspase-independent pathways emanating from the mitochondria are able to kill cells, a scenario that is played out by several recent studies discussed below.
Release of apoptosis-inducing factor Apoptosis-inducing factor AIF is a kD flavoprotein that resembles bacterial oxidoreductase and resides in the mitochondrial intermembrane space Susin et al. Upon induction of apoptosis, AIF translocates from the mitochondria to the nucleus and causes chromatin condensation and large-scale DNA fragmentation Susin et al.
These effects are independent of caspases and the oxidoreductase activity of AIF Miramar et al. Deficiency of AIF has profound effects in animal development. Disruption of AIF in mice prevents the normal apoptosis necessary for the cavitation of embryoid bodies in the embryo Joza et al. This very early apoptotic event is essential for mouse morphogenesis. Moreover, embryonic stem cells lacking AIF are resistant to cell death after vitamin K3 treatment and serum starvation Joza et al.
Because AIF is also an oxidoreductase that may play an important role in normal mitochondrial physiology, it is not clear whether the observed phenotype in the AIF KO mouse embryos is caused entirely by the elimination of the apoptotic activity of AIF or because of the loss of oxidoreductase function of AIF as well. What remains to be worked out is the biochemical mechanism by which AIF induces large-scale DNA fragmentation and chromatin condensation.
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Release of endonuclease G Endonuclease G EndoGa known kD nuclease in the mitochondria, was purified recently from the supernatant of mouse mitochondria that had been treated with caspaseactivated Bid tBida condition that mimicked the initiation of cell death after activation of the cell surface death receptor Li et al. EndoG is encoded by a nuclear gene, translated in the cytosol, and imported subsequently into the mitochondria Cote et al. It has been proposed that it participates in mitochondrial replication by eliminating RNA primers for the initiation of mitochondrial DNA synthesis Cote et al.
However, this proposal has been challenged by three experimental observations. Third, EndoG is specifically and quantitatively released from the mitochondria together with the other apoptogenic proteins in the intermembrane space. Under the same condition, the mitochondrial matrix protein mtHsp70 remains in the mitochondria Li et al. Therefore, at least a substantial portion of EndoG must be located in the mitochondrial intermembrane space, not in the matrix where DNA replication takes place.
The identification of AIF and EndoG indicates that apoptosis can proceed in the absence of caspase activity when the mitochondria are damaged. In this case, release of AIF and EndoG from mitochondria starts an apoptotic program parallel to caspase activation.
The role of EndoG in apoptosis is apparently conserved from worms to mammals. Using a suppressor screen for the active C.
CPS-6 protein is localized in the mitochondria and exhibits striking similarity in sequence and biochemical properties to the mammalian EndoG Parrish et al. These results indicate EndoG might represent an ancient evolutionarily conserved pathway. Additional studies are needed to clarify this issue. The release of cytochrome c and other apoptogenic proteins from mitochondria is known to be regulated by the Bcl-2 family of proteins.
The pro-death members of this group of protein promote the release of these apoptogenic factors whereas the anti-death members prevent it for review, see Korsmeyer et al. Regulation of mitochondrial apoptotic signals Translocation of the BH3-only family of proteins to mitochondria The BH3-only family of proteins share sequence homology with Bcl-2 only in the BH3 domain, an amphipathic helix required to interact with other Bcl-2 family members Huang and Strasser These proteins are normally located in other cellular compartments and translocate to the mitochondria in response to apoptotic stimuli.
Once translocated to the mitochondria, they cause mitochondrial damage and release of apoptogenic proteins by interacting with other members of the Bcl-2 family.