Researching Mitochondrial Roles in Apoptosis and Other
Cellular Processes
There is a burgeoning interest in the scientific community to fully define the roles
of mitochondria in cellular processes, particularly apoptosis (reviewed in 1). Apoptosis
is a complex process that can be induced by many different factors, which, in turn,
act through various cell death signaling pathways. The role of the mitochondria
could potentially vary and may be dependent on a variety of factors including mode
of apoptosis induction, cell type, or cell status with respect to the cell cycle, state
of differentiation, development, normalcy or pathology. Two views of the mode of
action are emerging. For example, there is an abundance of data suggesting that
mitochondria play a critical role in apoptosis by releasing cytochrome c and other
proteins that are essential for the activation of pro-caspase-9 and the execution of
apoptosis. In this scenario, mitochondrial-activated caspase-9 activates caspase-3.
Caspase-3 is often referred to as the primary executioner of apoptosis because it
cleaves multiple downstream proteins leading to a loss of cellular structure and
function, and ultimately cell death. Hence, one hypothesis supports the view that
mitochondria are the primary triggers of cell death rather than the caspases.
Other data suggest that mitochondria act more as facilitators rather than essential
players of apoptosis. For example, some signals may route to caspase activation
without first involving the mitochondria, and thereby the activated caspases may
target the mitochondria along with other cellular components. In this model, the
caspases would be the primary triggers of cell death, and mitochondria, along with
mitochondrial-linked caspase-9, would contribute to cellular demise rather than
being essential for it. Given the complexity of apoptosis, it is likely that there are
a number of mechanisms available to the cell for carrying out the process of apoptosis
(reviewed in 2). Assays designed to evaluate the functional status of mitochondria
are emerging as useful tools for helping to elucidate mitochondrial roles in apoptosis,
the cell cycle, and other cellular processes.
Particular focus has recently been given to assays designed to study the
mitochondrial membrane potential (Δψ) during apoptosis (reviewed in 3). Energy
released during the oxidation reactions in the mitochondrial respiratory chain is
stored as a negative electrochemical gradient across the mitochondrial membrane
and the Δψ is referred to as being polarized. Collapse of the Δψ results in a depolarized
Δψ, and is often, but not always, observed to occur early during apoptosis. For
example, collapse of the Δψ during apoptosis has been reported in a number of
studies, leading to a generalization that depolarization of the mitochondria is one
of the first events occurring during apoptosis and may even be a prerequisite for
cytochrome c release. However, this generalization is now a matter of debate and
there is data indicating that collapse of the Δψ does not always occur during apoptosis.
Thus, depolarization of the Δψ may be a cause of or be associated with apoptosis
in some, but not all systems. This is consistent with the concept that there are different
mechanisms available for cells to carry out the process of apoptosis. In addition
to apoptosis, changes in the Δψ have also been described during necrosis
(depolarization)4 and cell cycle arrest (hyperpolarization).5 Knowledge of the Δψ
and how it changes during apoptosis, necrosis, and the cell cycle may help to
clarify the role of the mitochondria in these and other cellular processes.
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