Intrinsic apoptotic pathway components (Mitochondrial apoptotic pathway)

The intrinsic apoptotic pathway, also known as the mitochondrial pathway, is a fundamental mechanism of programmed cell death initiated by internal cellular stressors such as DNA damage, oxidative stress, or growth factor withdrawal [1]. This pathway is primarily governed by the B-cell lymphoma 2 (BCL-2) family of proteins, which act as a rheostat to balance pro-survival and pro-death signals at the mitochondrial membrane [2]. When the balance shifts toward cell death, pro-apoptotic proteins BAX and BAK facilitate mitochondrial outer membrane permeabilization (MOMP), releasing cytochrome c and activating the caspase cascade [3]. In many cancers, this pathway is hijacked through the overexpression of anti-apoptotic proteins like BCL-2 or MCL-1, which prevents malignant cells from dying despite significant cellular damage [4]. Therapeutic intervention focuses on BH3 mimetics, such as Venetoclax, which inhibit these anti-apoptotic proteins to restore the apoptotic threshold and selectively eliminate cancer cells [5]. While highly effective in certain leukemias and lymphomas, targeting this pathway requires careful management of toxicities like tumor lysis syndrome and cytopenias [4, 5]. Sources: [1] StatPearls: Apoptosis Intrinsic Pathway (https://www.ncbi.nlm.nih.gov/books/NBK541071/) [2] Nature Reviews Molecular Cell Biology: The BCL-2 family: roles in cell survival and oncogenesis (https://www.nature.com/articles/nrm3820) [3] NIH/NCBI: The intrinsic pathway of apoptosis (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3108565/) [4] Journal of Hematology & Oncology: Targeting the BCL-2 family in cancer (https://jhoonline.biomedcentral.com/articles/10.1186/s13045-020-00954-z) [5] FDA: Venclexta (venetoclax) Prescribing Information (https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/208573s023lbl.pdf)

Other names

Mitochondrial pathway of apoptosisBCL-2 regulated pathwayIntrinsic apoptosisProgrammed cell death mitochondrial pathway

Drugs targeting this pathway, primarily BH3 mimetics, bind to the hydrophobic groove of anti-apoptotic BCL-2 family proteins (such as BCL-2, MCL-1, or BCL-XL). This binding displaces pro-apoptotic BH3-only proteins, which then activate the effector proteins BAX and BAK. Once activated, BAX and BAK oligomerize to cause mitochondrial outer membrane permeabilization (MOMP), leading to the release of cytochrome c into the cytosol. Cytochrome c binds to APAF-1 to form the apoptosome, which activates initiator caspase-9, subsequently triggering executioner caspases like caspase-3 and caspase-7 to carry out cell death [2, 4, 5].