Mitochondrial intrinsic apoptotic pathway (MIAP)

The mitochondrial intrinsic apoptotic pathway is a conserved cell death program initiated by internal stimuli such as DNA damage, oxidative stress, or metabolic deprivation (StatPearls, 2023). It is primarily regulated by the BCL-2 family of proteins, which act as a molecular switch to control the integrity of the mitochondrial outer membrane (Nature Reviews Molecular Cell Biology, 2019). Upon activation of pro-apoptotic members like BAX and BAK, the membrane undergoes permeabilization (MOMP), leading to the release of cytochrome c into the cytoplasm (Molecular Cell, 2020). This release triggers the formation of the apoptosome, which activates Caspase-9 and subsequently the executioner Caspase-3 to dismantle the cell (Cell Death & Differentiation, 2018). In many cancers, this pathway is inhibited through the overexpression of anti-apoptotic proteins such as BCL-2 or MCL-1, allowing cells to survive despite oncogenic stress (Journal of Clinical Oncology, 2020). Therapeutic intervention often involves BH3 mimetics, such as Venetoclax, which are small molecules designed to bind and neutralize these anti-apoptotic proteins to restore the apoptotic response (New England Journal of Medicine, 2016).

Other names

Intrinsic apoptosis pathwayMitochondrial pathway of apoptosisBCL-2-regulated apoptotic pathwayMitochondrial-mediated apoptosis

Inhibition of anti-apoptotic BCL-2 family proteins (e.g., BCL-2, BCL-XL, MCL-1) by BH3 mimetics to induce mitochondrial outer membrane permeabilization (MOMP), cytochrome c release, and subsequent caspase activation (Nature Reviews Drug Discovery, 2021).