What is the Intrinsic (Mitochondrial) Pathway?
The intrinsic pathway, also known as the mitochondrial pathway, is a key mechanism of
apoptosis or programmed cell death. It is triggered by internal cellular stress signals that lead to the activation of this pathway. The central role of mitochondria in this pathway makes it distinct from the
extrinsic pathway of apoptosis, which is initiated by external signals.
How Does the Intrinsic Pathway Initiate?
The intrinsic pathway is typically initiated by various intracellular stress signals such as DNA damage, oxidative stress, and other forms of cellular injury. These stress signals lead to the activation of pro-apoptotic members of the
Bcl-2 family of proteins, such as
Bax and
Bak. These proteins translocate to the mitochondria, where they promote the release of
cytochrome c from the intermembrane space into the cytosol.
What Are Caspases and Their Function?
Caspases are a family of protease enzymes that play essential roles in apoptosis. In the intrinsic pathway, initiator caspases such as caspase-9 are first activated, which then cleave and activate effector caspases like caspase-3. These effector caspases execute the apoptotic program by cleaving various cellular substrates, leading to the characteristic morphological changes of apoptosis, such as
cell shrinkage,
nuclear fragmentation, and
DNA fragmentation.
What Regulates the Intrinsic Pathway?
The intrinsic pathway is tightly regulated by pro-apoptotic and anti-apoptotic members of the Bcl-2 family. Anti-apoptotic proteins such as
Bcl-2 and
Bcl-xL work to inhibit the activation of Bax and Bak, thus preventing the release of cytochrome c. Conversely, pro-apoptotic proteins like Bax, Bak, and
BH3-only proteins promote apoptosis by facilitating mitochondrial outer membrane permeabilization.
Applications and Implications
Understanding the intrinsic pathway has therapeutic implications. For example, targeting Bcl-2 family proteins with specific inhibitors can induce apoptosis in cancer cells. Similarly, protecting neurons from apoptosis by modulating this pathway can have potential benefits in treating neurodegenerative diseases. In histological studies, observing the activation of the intrinsic pathway can provide insights into the pathological state of tissues and cells.
