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First published online May 30, 2008
Journal of Experimental Biology 211, 1829-1840 (2008)
Published by The Company of Biologists 2008
doi: 10.1242/jeb.000299
Commentary |
Mitochondria in energy-limited states: mechanisms that blunt the signaling of cell death
Division of Cellular, Developmental and Integrative Biology, Department of Biological Sciences, Louisiana State University, Baton Rouge, LA 70803, USA
* Author for correspondence (e-mail: shand{at}lsu.edu)
Accepted 20 March 2008
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Summary |
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 TOP Summary Introduction: survival during...Categories of cell deathMitochondrial involvement in...Energy status and cell...Physiological stress and...Specific requirements for ATP...Impact of mitochondrial poration...Concluding comments and future...References |
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Key words: apoptosis, necrosis, permeability transition pore, metabolic depression, anoxia, diapause, caspase activation
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Introduction: survival during energy-limited states |
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TOPSummaryIntroduction: survival during...Categories of cell deathMitochondrial involvement in...Energy status and cell...Physiological stress and...Specific requirements for ATP...Impact of mitochondrial poration...Concluding comments and future...References |
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;
Hand and Hardewig, 1996;
Hochachka and Guppy, 1987;
Lutz and Milton, 2004;
Storey and Storey, 2007), or
when hypometabolism is ontogenetically programmed, as during entry into
diapause. Diapausing organisms become hypometabolic even when environmental
conditions exist that normally would promote active metabolism and development
(Denlinger, 2002;
Hand et al., 2001;
Lees, 1955;
Reynolds and Hand, 2004;
Tauber and Tauber, 1976). It
is clear that the degree of metabolic depression is tightly correlated with
survivorship during energy-limited states like anoxia (e.g.
Hand, 1998). When the primary
metabolic pathway for ATP production (oxidative phosphorylation) is blocked,
for example by the absence of an electron acceptor, energy utilization must be
curtailed simultaneously. Otherwise, survival would be brief. Some animals
like embryos of the brine shrimp, Artemia franciscana, exhibit
profound metabolic depression and survive anoxia at room temperature for years
(Clegg, 1997) with no evidence
of apoptotic or necrotic cell death.
Many requirements for prolonged metabolic depression have been documented.
Gene expression is restricted because the manufacture of new macromolecules is
simply too expensive to maintain. Thus one observes the arrest of DNA
transcription (Eads and Hand,
2003b; Hardewig et al.,
1996; van Breukelen and Hand,
2000) and protein synthesis
(Fraser et al., 2001;
Hofmann and Hand, 1990;
Hofmann and Hand, 1994;
Kwast and Hand, 1996a;
Kwast and Hand, 1996b;
Land et al., 1993;
Land and Hochachka, 1994;
Pakay et al., 2003;
Podrabsky and Hand, 2000;
Wieser and Krumschnabel,
2001), and the extension of protein and mRNA half-lives
(Anchordoguy and Hand, 1995;
Anchordoguy and Hand, 1994;
Anchordoguy et al., 1993;
Eads and Hand, 2003a;
van Breukelen et al., 2000).
Channel arrest and other mechanisms to depress passive ion leak have been
observed at both the plasma and mitochondrial membranes
(Boutilier and St-Pierre,
2002; Buck and Hochachka,
1993; Gnaiger et al.,
2000; St-Pierre et al.,
2000). But unless depression of ion leakage is essentially total
(highly improbable), ionic disturbances like calcium overload in the
intracellular compartment will eventually occur and compromise of the
mitochondrial membrane potential is likely. Dissipation of ion gradients
(Covi and Hand, 2005;
Covi and Hand, 2007;
Covi et al., 2005) may occur
when energy flow is restricted to the point that ion transport across
membranes cannot keep up with passive ion leak. Such conditions are precisely
the ones that unavoidably trigger the initiation of apoptosis in mammalian
species. So how do some animals survive energy-limited states for days, weeks
and years?
Survival presumably requires that unwanted initiation of cell death, in any
of its various forms, is blunted or precluded. The focus of this commentary is
to consider the role of the mitochondrion in cell death processes, to
highlight fundamental similarities and differences in the regulation of cell
death that exist across phylogenetically diverse groups, and to evaluate
recent information that indicates `putting the brakes' on apoptosis is a
critical event for cell survival during energy-limited states. Current data do
not permit a comprehensive evolutionary analysis of the regulation of cell
death (cf. Zmasek et al.,
2007). However, an emerging picture is that some regulatory
systems for controlling cell death are more sensitive to energy disruption
than others. For example, a relatively modest compromise in calcium
homeostasis may trigger apoptosis in mammals, whereas severe energy limitation
may not initiate apoptosis in certain non-mammalian species. A character
trait, like prolonged tolerance to anoxia, may be a consequence, in part, of
the specific characteristics of apoptosis that are operative across species.
Functional trade-offs in environmental tolerance may have occurred in parallel
with the evolution of diversified pathways for the signaling of cell death in
eukaryotic organisms.
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Categories of cell death |
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TOPSummaryIntroduction: survival during...Categories of cell deathMitochondrial involvement in...Energy status and cell...Physiological stress and...Specific requirements for ATP...Impact of mitochondrial poration...Concluding comments and future...References |
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). With
an increased understanding of the multiple biochemical subroutines leading to
cell death, especially in mammals, more mechanism-based definitions have
appeared, sometimes leading to, in our opinion, less appealing constructs such
as `programmed necrosis' (Edinger and
Thompson, 2004; Melino et
al., 2005). Regardless of the specific category, cells eventually
pass a point of no return (when rescue is no longer possible), which may or
may not coincide with bioenergetic catastrophe depending on the specific cell
death pathway executed. Biochemical reactions that occur after the point of no
return may be either completely unregulated or highly orchestrated for some
interval of time.
Apoptosis, necrosis, autophagy
Up to 11 different types of cell death have been defined, and the
classification of cell death subroutines is an ongoing subject
(Melino et al., 2005). For
our purposes here, we will distinguish two major forms of cell death:
programmed cell death (PCD) and necrosis. As the name denotes, PCD involves
the execution of a genetic program, requires at least some minimal level of
ATP to be executed in an orderly fashion and is characterized by cell
shrinkage (Table 1). The cell
is destroyed without the release of breakdown products into the extracellular
space. Necrosis is characterized by a more severe disruption of bioenergetics,
cellular swelling and eventual rupture. In contrast to PCD, cellular contents
are released during necrosis and can inflame/activate other neighboring cells,
thereby spreading the necrotic region. While autophagy is considered by some
as a distinct type of PCD, it is in our view more appropriately viewed as a
rescue mechanism in times of starvation, when the cell recycles internal
components within double-membrane vesicles for the purpose of nutritional
gain. Under severe nutrient limitation, cell death may occur simultaneously
with autophagy, rather than as a result of autophagy
(Lum et al., 2005).
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Extrinsic versus intrinsic pathway to apoptosis in mammals
Two initiation pathways are triggered by different events to promote
apoptosis in mammals. The extrinsic pathway is triggered through ligation of
death receptors resident in the plasma membrane that transmit the death signal
into the interior of the cell (Tran et
al., 2004). This pathway frequently serves as a mechanism to
remove cells during development, differentiation and tissue remodeling. The
intrinsic pathway occurs as a response to moderate perturbation of
intracellular homeostasis by various cellular stresses [e.g. increased
reactive oxygen species (ROS) formation, xenobiotics, hypoxia/anoxia, viral or
bacterial proteins, and accumulation of misfolded proteins]
(Ferri and Kroemer, 2001). The
mitochondrion is an important integrator of both pathways (although not
essential for all modes of extrinsic cell death), and plays a leading role in
the amplification of the death signal.
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Mitochondrial involvement in cell death and comparison of pathways |
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TOPSummaryIntroduction: survival during...Categories of cell deathMitochondrial involvement in...Energy status and cell...Physiological stress and...Specific requirements for ATP...Impact of mitochondrial poration...Concluding comments and future...References |
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), but it
was in 1996–1997 that a major expansion of our understanding occurred,
when it became clear mitochondria were not just bioenergetic organelles but
also controlled life and death decisions in the cell
(Liu et al., 1996;
Yang et al., 1997). The
fundamental step of cytochrome c (cyt-c) release by
mitochondria in the progression of mammalian apoptosis sparked the realization
that mitochondria play a critical gatekeeper role.
In order to appreciate evolutionary differences that may contribute to the
sensitivity of cell death activation to energy limitation, we will briefly
describe the apoptotic machinery for the three most well-studied systems,
those of Caenorhabditis elegans, Drosophila melanogaster and
mammalian cells. The intuitive notion that apoptotic networks increase in a
linear way from simple to complex, as one moves from
cnidarian–bilaterian ancestors to nematodes, flies and vertebrates, is
apparently incorrect (Zmasek et al.,
2007). Rather, there have been numerous losses of apoptotic
paralogs among the apoptosome-forming proteins, and both losses and expansions
in Bcl-2 and caspase families. Different members of these families led to the
extant proteins represented across these groups and may explain some of the
functional differences in proteins that once were thought to be orthologous
(Zmasek et al., 2007). Thus,
the homologies drawn below are for the most part meant to imply functional
similarity.
The mitochondrial contribution to the death program in C. elegans
is only recently becoming appreciated
(Rolland and Conradt, 2006).
In response to a death stimulus, the pro-apoptotic Bcl-2 family protein EGL-1
interacts with CED-9, which is a mitochondria-bound, anti-apoptotic homolog of
mammalian Bcl-2 (Fig. 1A). The
interaction causes the displacement and release of a CED-4 dimer. CED-4 is a
mammalian homolog of APAF-1 and in turn activates the caspase3 homolog CED-3
(Yan et al., 2005). During
this process, fragmentation of the mitochondrial network can be observed
(Jagasia et al., 2005), and
two pro-apoptotic factors are released. Release of the AIF homolog WAH-1
(Wang et al., 2007;
Wang et al., 2002) and the
presence of CPS-6 [an endonuclease G (EndoG) homolog
(Parrish et al., 2001)]
underscores the importance of mitochondrial involvement in apoptosis.
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In D. melanogaster (Fig.
1B) cell death is largely regulated by the
reaper, hid and
grim gene products (RHG killer proteins) and their
inactivation of IAPs, a class of proteins not found in C. elegans
that inhibit caspase activity (Hay et al.,
2004; Kornbluth and White,
2005). Furthermore, two Bcl-2 proteins with modest pro- and
anti-apoptotic features are found (BUFFY, DROB-1) that localize to the
mitochondria (Igaki and Miura,
2004) and possibly impact mitochondrial functions and participate
in stress-induced PCD (Sevrioukov et al.,
2007). Highly conserved homologs of AIF and EndoG that contain
mitochondrial target sequences are found in Drosophila (accession
number NP_722765 and NP_610737, respectively), but thus far functional roles
in PCD are undefined. However, recent reports underscore the importance of the
mitochondrial involvement in apoptosis by demonstrating fragmentation
(Abdelwahid et al., 2007) as
well as permeabilization of the mitochondrial network and release of the
pro-apoptotic protein DmHtrA2, which inactivates IAPs
(Challa et al., 2007;
Igaki et al., 2007). A
pro-apoptotic action of cyt-c is controversial
(Arama et al., 2006;
Means et al., 2005) and may
be restricted to certain cell types or tissues in Drosophila. As in
C. elegans, activation of caspases can be mediated by an adaptor
platform, the CED-4 homolog DARK (Yu et
al., 2006). DARK interacts with the initiator caspase DRONC, an
ortholog of the mammalian caspase 9
(Mills et al., 2006), and
several downstream executor caspases have been described
(Hay and Guo, 2006).
At least five factors that reside in the mammalian mitochondrion are
involved in caspase-dependent and -independent PCD
(Saelens et al., 2004)
(Fig. 1C). Depending on the
specific nature of the death signal, these factors are released through
permeabilization of the outer, or inner and outer, mitochondrial membrane
(Kroemer et al., 2007). This
process is accompanied by an extensive fragmentation of the mitochondrial
network that happens prior to caspase activation
(Youle and Karbowski, 2005).
After release from the mitochondrion, the NADH-oxidase AIF and the
endonuclease EndoG translocate to the nucleus where they are involved in
chromatin condensation and DNA degradation
(Low, 2003;
Modjtahedi et al., 2006).
Other effectors impact the PCD machinery in a caspase-specific fashion. The
RHG analog SMAC/DIABLO releases caspases from inhibition by IAPs. IAPs are
intrinsic regulators of the caspase cascade and are the only known endogenous
proteins that regulate the activity of both initiator (caspase 9) and effector
(caspase 3, caspase 7) caspases (Liston
et al., 2003). The serine protease Omi contributes to PCD in two
ways. Omi neutralizes inhibition of caspases by IAPs, and also contributes to
caspase-independent apoptosis through its protease activity
(Saelens et al., 2004).
Discovery of the Janus-faced nature of cyt-c reshaped our picture of
the mitochondrion's role in life and death more than any other factor
(Liu et al., 1996). Inside
the mitochondrion, cyt-c is essential for oxidative phosphorylation,
but after release into the cytoplasm, it initiates the assembly of the
apoptosome, i.e. the molecular machinery that activates caspase 9.
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Energy status and cell death |
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TOPSummaryIntroduction: survival during...Categories of cell deathMitochondrial involvement in...Energy status and cell...Physiological stress and...Specific requirements for ATP...Impact of mitochondrial poration...Concluding comments and future...References |
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;
de Graaf et al., 2002;
Izyumov et al., 2004;
Marton et al., 1997;
Vander Heiden et al., 1999);
exceptions exist (e.g. Atlante et al.,
2005)]. This relationship with ATP level exists despite the fact
that there are a number of steps in the apoptotic pathway that actually
require ATP (see below, `Specific requirements for ATP in cell death').
However, it is appropriate to point out that a major drop in cellular ATP can
occur without limiting the activities of many of these steps, due to the
micromolar Km values for the enzymes involved (cf.
Skulachev, 2006) and the
rather high ATP binding affinities for non-catalytic proteins that participate
in the process (Riedl et al.,
2005). Further, the amount of ATP needed to permit the progression
of apoptosis is actually quite small, and the source of ATP is not critical,
e.g. it can be produced from either glycolysis or oxidative phosphorylation
(Nicotera et al., 2000;
Skulachev, 2006). Thus,
modest compromise in mitochondrial function (and a concomitant drop in ATP)
does not necessarily dictate that necrosis will be favored and apoptosis
disfavored. Nevertheless it is true that necrotic cell death is typically
observed under conditions of severe ATP depletion in mammalian systems
(Atlante et al., 2005;
Eguchi et al., 1997;
Leist et al., 1997;
Nicotera et al., 2000;
Nicotera et al., 1998;
Nicotera and Melino,
2004).
Skulachev and colleagues have studied the interplay in HeLa cells between
cellular ATP levels and the occurrence of apoptosis versus necrosis
(Izyumov et al., 2004). These
authors report that not only is the magnitude of the ATP drop important for
favoring one form of cell death over the other, but also the length of time
HeLa cells experience compromised ATP levels is a determining factor, with
longer exposures being more conducive to necrosis. Such linkages to both the
duration and degree of ATP depression were first shown for Jurkat cells
(Leist et al., 1997), an
immortalized line of human T lymphocytes. When interpreting cell death studies
with immortalized cell lines, a cautionary note it is that such cells
typically display an altered metabolic poise (more glycolytic based), and the
features of cell death are apt to differ from primary cells or tissues.
If placed in the perspective of the overall energy budget for a cell, the
ATP requirements for operating the cell death pathways are likely to be small.
The main consumers of cellular energy in the basal state are three processes.
(1) The metabolic cost of active transport by the
Na+/K+-ATPase for the maintenance of ion gradients
averages 36% [range 15–58% (Covi and
Hand, 2007)] of the basal metabolic rate across many cell types
(Hand and Hardewig, 1996;
Rolfe and Brown, 1997).
Similarly, the cost of maintaining the proton gradient across the
mitochondrial inner membrane, i.e. offsetting the proton leak, is also
estimated to be quite substantial, accounting for 20–40% of the
respiration rate of hepatocytes isolated from a rat and a lizard
(Brand et al., 1994). Thus,
over half the cell's energy can be devoted to processes of ion transport
alone. (2) Under resting conditions, the metabolic cost of protein synthesis
ranges between 18 and 26% in various tissues and cell types
(Hawkins, 1991), and even
higher values are observed for tissues during growth or increased biosynthetic
activity (Land et al., 1993).
The cost of ubiquitin-dependent protein degradation is sizable as well
(Land and Hochachka, 1994).
(3) Finally, DNA transcription and replication are responsible for up to 10%
of basal cellular metabolism (Rolfe and
Brown, 1997). Consequently, initiation and execution of apoptosis
are unlikely to represent even a noticeable fraction of the energy budget. In
the latter phases of cell death, when various physiological processes have
been disrupted, the relative cost of cell death processes within the cellular
energy budget undoubtedly increases. Unfortunately, a quantitative inventory
of how much ATP is utilized during apoptosis is not available
(Chiarugi, 2005).
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Physiological stress and mitochondrial permeabilization |
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TOPSummaryIntroduction: survival during...Categories of cell deathMitochondrial involvement in...Energy status and cell...Physiological stress and...Specific requirements for ATP...Impact of mitochondrial poration...Concluding comments and future...References |
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). Thus, if the sarco-endoplasmic reticulum
Ca2+-ATPase (SERCA) loses its ability to scavenge calcium from the
cytoplasm, free calcium in the cytoplasm will rise precipitously
(Walter and Hajnoczky, 2005).
High cytoplasmic calcium has stimulatory effects at multiple steps in cell
death pathways (Fig. 2; see
`Mitochondrial permeability transition pore (MPTP)' and `Specific requirements
for ATP in cell death' below).
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;
Gunter et al., 2004). Because
the maximal rate of calcium efflux is much lower than calcium uptake,
mitochondria exposed to high calcium are susceptible to the hazard of calcium
overload (Bernardi, 1999).
Calcium overload in the matrix can lead to opening of the mitochondrial
permeability transition pore (MPTP) in mammalian cells
(Fig. 2; see `Mitochondrial
permeability transition pore (MPTP)' below).
Oxidative stress as a result of the generation of ROS is another important
initiator/facilitator of cell death pathways, and a sizable fraction of
cellular ROS is generated by mitochondria. Yet, in the metabolic states being
considered in the present commentary, mitochondrial electron transport is
greatly downregulated (e.g. Clegg et al.,
1996; Gnaiger et al.,
2000; Hand, 1998;
Reynolds and Hand, 2004). ROS
generation by the mitochondrion cannot occur under anoxia due to the absence
of the substrate for ROS and a terminal electron acceptor to support electron
transport. Likewise, during diapause mitochondrial respiration can be
depressed by as much as 97% by unidentified mechanisms
(Clegg et al., 1996;
Reynolds and Hand, 2004).
Thus, in neither case is the generation of ROS an issue. For further
information on the interplay between oxidative stress and cell death, a number
of useful reviews are available (Brookes
et al., 2004; Kakkar and
Singh, 2007; Orrenius et al.,
2007; Ryter et al.,
2007).
Mitochondrial permeability transition pore (MPTP)
Basic features of the regulated MPTP in mammals
If mammalian mitochondria are exposed to high calcium concentrations in the
presence of the co-activator Pi
(Fig. 2), especially when
accompanied by adenine nucleotide depletion and a reduced inner membrane
potential (Petronilli et al.,
1993a), a large swelling can be observed that is associated with
the uncoupling of respiration and release of cyt-c
(Gunter and Pfeiffer, 1990;
Halestrap et al., 2000;
Haworth and Hunter, 1979).
These phenomena are due to a sudden increase in permeability of the inner
mitochondrial membrane to solutes with a molecular mass of up to 1500 Da, a
phenomenon known as the mammalian mitochondrial permeability transition
(Bernardi, 1996;
Hunter et al., 1976). The
swelling of the matrix compartment causes rupture of the outer mitochondrial
membrane and release of multiple pro-apoptotic factors from the intermembrane
space. The mitochondrial permeability transition is mediated by a
multi-protein complex, which can be defined as a voltage-dependent,
cyclosporin A-sensitive and calcium-activated inner membrane channel
(Bernardi et al., 1999).
The molecular composition of the MPTP is still not established.
Historically, the minimum constituents of the regulated MPTP were proposed to
be the voltage-dependent anion channel (VDAC), the adenine nucleotide
translocators (ANTs), and the peptidyl-prolyl cistrans isomerase (PPI)
cyclophilin D (Crompton, 1999;
Halestrap and Brennerb, 2003;
Pliyev and Gurvits, 1999).
Although the sensitivities to inducers are altered, recent evidence has shown
that the MPTP can form a functional complex in the absence of ANTs
(Kokoszka et al., 2004),
without VDAC (Baines et al.,
2007; Krauskopf et al.,
2006), and without cyclophilin D
(Baines et al., 2005;
Basso et al., 2005). Not
surprisingly, as a result alternative compositional models have been proposed
(Bernardi et al., 2006;
He and Lemasters, 2002;
Rasola and Bernardi,
2007).
Non-specific (unregulated) pore
He and Lemasters (He and Lemasters,
2002) proposed a two-step mode of mercury-induced mitochondrial
permeabilization: activation of the regulated MPTP by low mercury and
unspecific `damage' of membrane proteins at higher mercury, leading to an
unregulated pore. More than 30 mitochondrial carriers have been described
(Passarella et al., 2003),
and mercury is known to interact with several of these and transform their
properties to be more channel like and non-specific
(Dierks et al., 1990a;
Dierks et al., 1990b). In the
absence of a defined macromolecular composition for the regulated MPTP, it is
possible that oxidation/degradation of variable combinations of mitochondrial
proteins that then associate and in some manner permeabilize the inner
membrane might represent a plausible explanation for even the regulated pore.
However, for such a scenario to hold, it must account for specific pore
opening by the physiological inducers calcium plus phosphate, the specific
inhibition by cyclosporin A, and voltage dependency.
Non-mammalian MPTPs
Despite an enormous amount of literature on the mammalian MPTP, little is
known about MPTPs in non-mammalian species. In vitro studies have
shown that in lipid vesicles, reconstituted ANTs from Neurospora
crassa can form mega-channels that exhibit characteristics similar to the
MPTP (response to calcium, ADP and bongkrekic acid)
(Brustovetsky et al., 2002).
However, the occurrence of an in vivo MPTP in N. crassa
mitochondria was not examined. Mitochondria from the yeast Saccharomyces
cerevisiae exhibit a permeability transition pore that is inhibited by
ADP and has a size exclusion comparable to mammalian MPTPs, but the yeast pore
is not induced by calcium and is not cyclosporin A sensitive
(Jung et al., 1997). In
addition, a calcium-induced transition could not be found in mitochondria from
the yeast Endomyces magnusii
(Deryabina et al., 2004).
Investigations of purified potato and wheat mitochondria show a
calcium-sensitive permeability transition that is inhibited by cyclosporin A
in the presence of dithiothreitol (Arpagaus
et al., 2002; Virolainen et
al., 2002). Isolated liver mitochondria from the great green goby
(Zosterisessor ophiocephallas) show calcium-induced swelling if
incubated in the presence of Pi, but the amount of calcium
required to induce the mitochondrial permeability transition was substantially
higher than that needed for mitochondria from rat liver
(Toninello et al., 2000).
While data are not fully conclusive, a MPTP may exist in liver mitochondria
from the Baltic lamprey Lampetra fluviatilis
(Savina et al., 2006).
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), it is
nevertheless inconceivable that the mitochondrial 
is not
eventually compromised during prolonged anoxia, which in this animal can be
tolerated for several years at room temperature
(Clegg, 1997), or during
months of diapause. A decline in membrane potential increases the probability
of MPTP opening by calcium (Bernardi,
1992; Petronilli et al.,
1993a; Petronilli et al.,
1993b). A large increase in intracellular calcium is a hallmark
change observed in many cells exposed to anoxia
(Hochachka, 1986). Thus a
question arose as to how A. franciscana avoided apoptotic and
necrotic cell death during long-term anoxia, an environmental challenge that
should foster the release of cyt-c and other pro-apoptotic factors
from mitochondria due to MPTP activation.
We showed that mitochondria from A. franciscana possessed VDAC,
ANT and cyclophilin D, yet the traditional assay used to measure opening of
the MPTP (mitochondrial swelling) clearly showed that the pore did not respond
to the addition of calcium and phosphate in de-energized mitochondria
(Fig. 3)
(Menze et al., 2005b). In
contrast, calcium addition to energized mitochondria from A.
franciscana actually promoted an increase in absorbance, which was
apparently due to their extensive capacity for calcium loading
(Fig. 3). The formation of
calcium phosphate complexes in the matrix causes an increase in the refractive
index (Nicholls and Chalmers,
2004). In comparison, rat liver mitochondria showed the typical
pattern of rapid swelling in response to calcium plus phosphate
(Fig. 3), which could be
blocked by cyclosporin A. Thus, by this measure, a calcium-regulated opening
of the MPTP was not detectable in A. franciscana mitochondria. Not
surprisingly, based on this lack of swelling, incubation of energized
mitochondria from A. franciscana with 1 mmol l–1
calcium for 30 min did not induce the release of cyt-c
(Fig. 3, lower panel). Use of
positive controls (alamethicin, an artificial pore-forming agent; treatment
with high mercury concentrations) confirmed that mitochondria from A.
franciscana intrinsically possessed the capacity for swelling
(Menze et al., 2005b). In
other words, swelling could be artificially stimulated and measured, but known
inducers of the regulated MPTP were without effect.
To confirm the apparent absence of MPTP opening in A. franciscana,
we measured the kinetics of calcium-induced calcium release in mitochondria
isolated from both A. francsicana and rat liver by using a
fluorescent probe that reports external free calcium
(Fig. 4)
(Menze et al., 2005b).
Mitochondria from the two species differed dramatically in their responses to
exogenously added calcium. Calcium additions of 0.1 mmol l–1
and higher to energized rat mitochondria promoted an increase in fluorescence
well above that seen in the absence of mitochondria (control value), a result
that indicates the opening of the MPTP and release of calcium stores from the
matrix (Fig. 4B). In contrast,
energized mitochondria from A. franciscana
(Fig. 4A) were able to reduce
the external calcium concentration, compared with controls, across the entire
range of experimental calcium. Thus the capacity for calcium uptake by
mitochondria from A. franciscana was far greater than that seen for
rat liver mitochondria. Second, although a clear calcium-dependent opening of
the MPTP occurred at 0.1 mmol l–1 calcium in rat liver
mitochondria, no calcium-dependent MPTP opening was indicated for A.
franciscana mitochondria, because the calcium level in the presence of
energized mitochondria never reached, much less exceeded, the controls (no
mitochondria). Thus calcium-induced calcium release, a hallmark of MPTP
opening, did not occur at any level of exogenously added calcium.
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).
Second, a similar recalcitrant MPTP has been documented in a ghost shrimp,
Lepidophthalmus louisianensis (J. Holman and S.C.H., unpublished
observations). Finally, indirect evidence suggests that a regulated MPTP may
be absent in mitochondria from the oyster Crassostrea virginica
(Sokolova et al., 2004).
Specifically, cadmium up to 1000 µmol l–1 [sufficent to
open the mammalian MPTP in a cyclosporin A-sensitive manner
(Belyaeva et al., 2002)] in
the presence of phosphate did not cause swelling of isolated mitochondria, but
physiological inducers were not evaluated. The molecular explanation for the
absence of a regulated MPTP in A. franciscana is currently under
investigation and could inform us of new mechanisms for regulating the
pore.
Mitochondrial outer membrane permeabilization (MOMP)
A complex interplay between the pro- and anti-apoptotic proteins belonging
to the Bcl-2 family controls the permeability of the outer mitochondrial
membrane in mammals. Proteins in this family are characterized by the presence
of up to four Bcl-2 homology regions (BH1–4). Based on the presence of
these regions and the cellular function of the protein, Bcl-2 family proteins
are divided into three subfamilies: multi-domain anti-apoptotic (e.g. Bcl-2,
Bcl-xL), multi-domain pro-apoptotic (e.g. Bax, Bak) and pro-apoptotic BH3-only
proteins (e.g. Bid, Bad) (Gross et al.,
1999). The mechanism of MOMP is mediated by the pore-forming
proteins Bak and Bax (Fig. 1),
whose activation is promoted by BH3-only proteins. This activation could occur
either by direct binding to Bax/Bak, or indirectly by displacement of the
anti-apoptotic Bcl-2 subfamily members from Bax/Bak
(Willis and Adams, 2005). In
non-apoptotic cells Bak is tail-anchored to the outer mitochondrial membrane,
whereas Bax is mostly cytosolic
(Lucken-Ardjomande and Martinou,
2005; Youle and Strasser,
2008). During apoptosis Bax translocates to the mitochondrion
where it changes conformation and inserts into the outer mitochondrial
membrane (Hsu et al., 1997).
The precise mechanism by which MOMP is mediated is still unclear. The
predominant view is that Bax and Bak undergo conformational changes,
oligomerize and form pores in the outer mitochondrial membrane
(Antignani and Youle, 2006). To
complicate matters further, the tumor suppressor protein p53 can impact MOMP
by promoting in the nucleus expression of PUMA (a BH3-only protein)
(Fig. 1), which then releases
p53 from Bcl-xL, thereby freeing p53 to activate Bax in the cytoplasm
(Chipuk et al., 2005).
Loss of anti-apoptotic Bcl-2 family members under anoxia
Mammalian cell death during hypoxia/anoxia occurs via the
intrinsic pathway of apoptosis (Brunelle
et al., 2007; McClintock et
al., 2002; Shimizu et al.,
1995; Shroff et al.,
2007). Key regulators of apoptosis during anoxia are the Bcl-2
family proteins (Shimizu et al.,
1995). The pathway is initiated by the loss of function of the
pro-survival Bcl-2 family members Mcl-1 and Bcl-2/Bcl-xL, resulting in Bax- or
Bak-dependent release of cyt-c and subsequent caspase 9-dependent
cell death. A key member of the Bcl-2 family of pro-survival proteins, Mcl-1,
undergoes ubiquitin-dependent degradation by the proteasome. While the
mechanisms are currently ill-defined, it is suggested that inhibition of the
electron transport chain due to oxygen deprivation is in some way linked to
the negation of the pro-survival function of Bcl-2 family proteins.
One would predict that the above mechanism, if operative in A.
franciscana embryos, must be short-circuited under anoxia. At present
nothing is known about homologs of Bcl-2 family proteins in A.
franciscana. Whether or not pro-survival proteins similar to CED-9 in
C. elegans exist, and whether such proteins are involved in
anoxia-induced cell death is unclear. However, it is well established that
ubiquitin-dependent (proteosomal) degradation of proteins is acutely arrested
under anoxia in A. franciscana embryos
(Anchordoguy and Hand, 1995;
Anchordoguy and Hand, 1994). If
Bcl-2 family homologues are degraded in A. franciscana in a similar
way to that in mammals, then this inhibition of ubiquitin-dependent
degradation may be a potential mechanism by which initiation of
Bax–Bak-dependent MOMP is avoided under anoxia.
|
Specific requirements for ATP in cell death |
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TOPSummaryIntroduction: survival during...Categories of cell deathMitochondrial involvement in...Energy status and cell...Physiological stress and...Specific requirements for ATP...Impact of mitochondrial poration...Concluding comments and future...References |
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;
Chiarugi, 2005;
Eguchi et al., 1997;
Kass et al., 1996;
Leist et al., 1997;
Nicotera et al., 2000;
Nicotera et al., 1998;
Skulachev, 2006), although we
have argued that the absolute quantities and fluxes are modest and have been
over emphasized in recent literature. The inactivation of anti-apoptotic Bcl-2
by phosphorylation by JNK (c-Jun NH2 terminal kinase)
(Fan et al., 2000;
Yamamoto et al., 1999),
activation of pro-apoptotic factors Bad, Bim and Bmf
(Donovan et al., 2002;
Lei and Davis, 2003), and
other steps relying on covalent modification with ATP as a phosphate donor use
tiny amounts of ATP. The movement and fragmentation of mitochondria, which are
routinely associated with apoptosis, require the activities of ATPases and
GTPases, but estimates of energy consumption for such processes are
unavailable to our knowledge. For the extrinsic pathway of apoptosis,
ATP-driven nuclear import of apoptogenic factors from the cytoplasm is also an
energy-dependent step (Chiarugi,
2005; Yasuhara et al.,
1997). For assembly of the mammalian apoptosome, Apaf-1-dependent
activation of caspase 9 is maximal at 1 µmol l–1 ATP
(Riedl et al., 2005), which
may be compared with cellular levels of one to several millimolar ATP.
|
Where depression in ATP production rate may have significant physiological
impacts is on processes like ion transport that consume large quantities of
ATP. Restriction of active calcium uptake by SERCA into the ER may render the
pump unable to balance the loss of Ca2+ through release channels
(inositol-1,4,5-trisphosphate receptor–Ca2+ channel,
ryanodine receptor/Ca2+ channel) or leak pathways. A parallel
scenario can be developed for ATP limitation of the plasma membrane calcium
pump. The resultant rise in free cytoplasmic calcium has far-reaching effects
on cell death (Fig. 2).
Perturbation of the Na+/K+-ATPase by reduced ATP
availability is apparently key. Activation of apoptosis by exposing
lymphocytes or thymocytes to anti-Fas (which stimulates a plasma membrane
death receptor) promotes inactivation of the
Na+/K+-ATPase, thereby significantly decreasing
K+ uptake and irreversibly depolarizing the cell membrane
(Remillard and Yuan, 2004).
This depolarization activates voltage-dependent K+ and
Cl– channels, promoting cell shrinkage due to the accentuated
loss of KCl (Fig. 2). This drop
in intracellular KCl is also known to directly stimulate caspase activity and
thus apoptosis (see `Impact of mitochondrial poration on downstream events'
below). Finally, proteins whose functions are sensitive to adenylate ratios
(ATP/ADP in the case of ANT; AMP/ATP for the AMP-activated protein kinase),
proteins with low affinities for ATP, or proteins where the allosteric impact
of nucleotides (e.g. certain caspases) may fall in the millimolar range, could
all serve as ATP-sensing steps. Decreasing the ATP/ADP ratio can alter the
conformation of ANT and increase the probability of MPTP opening by calcium
(Bernardi et al., 2006).
|
|
Impact of mitochondrial poration on downstream events |
|---|
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TOPSummaryIntroduction: survival during...Categories of cell deathMitochondrial involvement in...Energy status and cell...Physiological stress and...Specific requirements for ATP...Impact of mitochondrial poration...Concluding comments and future...References |
|---|
). In
clear contrast to mammalian cells, caspase activation by cyt-c is
absent in A. franciscana embryos
(Fig. 5). As expected, extracts
obtained from human C3A cells responded with a sharp increase in caspase 3 and
a less pronounced increase in caspase 9 activity after addition of
cyt-c. Work on the assembly and function of DARK, the apoptosome of
D. melanogaster, has indicated that cyt-c is not required
for its in vitro assembly, nor is cyt-c incorporated into
the final structure (Yu et al.,
2006). Thus, our data are consistent with a view that the
apoptosome in arthropods can assemble and activate caspases in the absence of
cyt-c. Cyt-c participation is also absent in the activation
of meta-caspases in yeast cells, which do not even contain an Apaf-1 homolog
in their genome (Madeo et al.,
2002). Fully establishing the evolutionary pattern for the
involvement of cyt-c in the apoptotic cascade of eukaryotic organisms
would be instructive from multiple perspectives. Integration of cyt-c
signaling into the carefully balanced process of caspase activation requires
many steps beyond the acquisition of intracellular organelles like
mitochondria.
Caspase regulation
Despite the absence of a cyt-c effect, many basic features of
caspase regulation in mammals are observed in A. franciscana. High
intracellular nucleotide concentrations represent a critical pro-survival
condition that prevents caspase activation due to the interaction with both
cyt-c (Chandra et al.,
2006) and caspase 9 (Chereau
et al., 2005), whereas high intracellular potassium inhibits
apoptosome formation by binding to Apaf-1
(Cain et al., 2001). Both
regulatory effects are observed in A. franciscana, although the
mechanisms of action are likely to differ.
Multiple species of adenylates and guanylates impact the caspase activities
in A. franciscana (Menze and
Hand, 2007) and, moreover, there are differences in response
between diapause and non-diapause embryos to Mg2+-ADP
(Fig. 6). Analysis of the
IC50 value showed that inhibition by Mg-ADP is far greater in
diapause embryos (IC50=0.66 µmol l–1) than in
post-diapause embryos (IC50=44.4 µmol l–1).
This observation is apt to be of physiological relevance and may represent a
new mechanism to prevent caspase activation during cell stasis. In A.
franciscana embryos, ADP levels remain constant during diapause (J. A.
Covi, J. Reynolds and S.C.H., unpublished observations). Consequently, this
pattern could prevent caspase activation under energy limitation when ATP
levels fall. In mammalian systems a physiological role for ADP in caspase 9
regulation has not been reported (Chandra
et al., 2006; Chereau et al.,
2005), and ADP does not stimulate Apaf-1 activation of caspases
(Riedl et al., 2005).
Another novel feature of A. francsicana caspases is that GTP
inhibits caspase 9 activity, and the regulatory pattern for GTP on caspase 9
in A. franciscana embryos is very similar to that for ATP
(Menze and Hand, 2007).
Because intracellular GTP remains high (>2 mmol l–1) in
embryos exposed to anoxia (Stocco et al.,
1972), it could serve as a means to prevent maladaptive apoptosis
during oxygen deprivation that otherwise might occur during the precipitous
drop in ATP that occurs under anoxia
(Carpenter and Hand, 1986;
Stocco et al., 1972). The
remarkably high levels of soluble guanylates present in A.
franciscana embryos are a consequence of the huge stores of
P1,P4-diguanosine
5'-tetraphosphate (Gp4G) and its complex metabolic
interconversions (Finamore and Warner,
1963; Stocco et al.,
1972). The suggestion that in mammals GTP/dGTP may bind to
cyt-c, prevent apoptosome formation, and thereby indirectly inhibit
caspase activation (Chereau et al.,
2005) cannot explain the GTP effect in A. franciscana.
Rather, GTP apparently promotes a more direct inhibition by binding to caspase
9 or perhaps to the adaptor platform Apaf-1/Ced-4. Multiple mechanisms are in
place that could serve to `apply the brakes' to apoptosis during
energy-limited states in A. franciscana.
|
Concluding comments and future directions |
|---|
|
TOPSummaryIntroduction: survival during...Categories of cell deathMitochondrial involvement in...Energy status and cell...Physiological stress and...Specific requirements for ATP...Impact of mitochondrial poration...Concluding comments and future...References |
|---|
),
compromised adenylate status does not activate either death routine in animals
capable of severe metabolic arrest. The extended and simultaneous arrest of
oxidative phosphorylation and glycolytic flux experienced by A.
franciscana would be viewed as a `bioenergetic catastrophe'
(Kroemer et al., 2007) for
mammalian cells. Yet the 4000 gastrula-stage cells of A. franciscana
survive the condition under diapause and anoxia for months to years at room
temperature. To be sure, A. franciscana is not a `freak of nature'.
Numerous species from 34 of 35 major animal phyla display the capacity for
severe metabolic arrest (dormancy) at various points in their life cycles
(Crowe and Clegg, 1973).
Biological interpretations that place the findings from A.
franciscana in an evolutionary context are hampered by the paucity of
data on other tolerant species. Still, our current view is that
characteristics discussed here for A. franciscana (e.g. lack of a
functional MPTP) are apt to be features of many animal phyla. In contrast, the
regulatory mechanisms for cell death that have evolved in mammals may have
been linked to substantial trade-offs in tolerance to energy-limited
states.
Unresolved questions are what is the signaling/sensing process by which a
transient, moderate drop in ATP can stimulate initiation of apoptosis, or by
which a more severe, prolonged drop favors necrosis? Is the ATP effect direct
or indirect, i.e. mediated through an impact on another cellular process like
ion homeostasis? Understanding these mechanisms might eliminate much
controversy as to what governs progression along one versus another
divergent pathway to cell death (Newmeyer
and Ferguson-Miller, 2003). As we learn more about energy
requirements for various forms of cell death, distinctions among subtypes are
becoming blurred (Chiarugi,
2005). Evidence is building that the mitochondrial apoptotic
pathway may bifurcate at the post-mitochondrial level, with one branch being
caspase and ATP dependent, and another independent of both
(Chiarugi, 2005).
There are marked differences in A. franciscana mitochondria,
relative to those of mammals, in the MPTP and capacities for calcium uptake.
Further, caspase activation in A. franciscana does not rely on
cytrochrome c release from mitochondria, and its caspases show novel
and interesting responses to nucleotides and calcium that may blunt activation
that would readily occur under energy-limited conditions in mammalian cells.
Yet there are areas where more data are required in order to piece together an
integrated understanding of cell death pathways and their regulation in A.
franciscana. In addition to the MPTP, information is needed on the
regulation of MOMP via mechanisms comparable to Bax/Bak poration in
mammals. What other pro-apoptotic factors (aside from cyt-c) may be
potentially released by MOMP? How reliant is A. franciscana on IAPs
for controlling caspase activity? How well developed is crosstalk between the
ER and mitochondrion in A. franciscana, and are there features of
mitochondrial fragmentation that place constraints on mitochondrial-based
pathways for apoptosis? Such information will help explain how processes of
cell death are blunted during states of metabolic arrest, and it may lead to
new therapies for intervention to prevent cell death in disease states and
during biostabilization of mammalian cells
(Buchanan et al., 2005;
Crowe et al., 2005;
Elliott et al., 2006;
Hand and Hagedorn, 2008;
Liu et al., 2005;
Menze et al., 2005a).
|
Acknowledgments |
|---|
|
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TOPSummaryIntroduction: survival during...Categories of cell deathMitochondrial involvement in...Energy status and cell...Physiological stress and...Specific requirements for ATP...Impact of mitochondrial poration...Concluding comments and future...References |
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