Apoptotic caspases and mitochondrial apoptotic machinery

The apoptotic caspases and mitochondrial apoptotic machinery represent the core biochemical framework for programmed cell death (apoptosis). The mitochondrial, or intrinsic, pathway is regulated by the Bcl-2 family of proteins, which act as a rheostat to control mitochondrial outer membrane permeabilization (MOMP) [1]. Upon MOMP, Cytochrome c is released into the cytoplasm, where it binds Apaf-1 to form the apoptosome, subsequently activating the initiator Caspase-9 [2]. This leads to the activation of executioner caspases, primarily Caspase-3 and Caspase-7, which proteolytically cleave a wide array of cellular substrates to execute cell death [3]. In oncology, the evasion of apoptosis is a critical survival mechanism, frequently achieved through the overexpression of anti-apoptotic proteins like Bcl-2, making them high-priority therapeutic targets [4]. Drugs such as venetoclax (a BH3 mimetic) have been developed to inhibit Bcl-2, thereby restoring the apoptotic potential of malignant cells [5]. Conversely, in conditions like neurodegeneration or ischemia, excessive caspase activity leads to pathological cell loss, prompting the investigation of caspase inhibitors as neuroprotective agents [6].

Other names

Intrinsic apoptotic pathwayCaspase cascadeMitochondrial death machineryBcl-2 regulated apoptotic pathwayMOMP-mediated apoptosis

Inhibition of anti-apoptotic Bcl-2 family proteins, direct inhibition of caspase proteolytic activity, and induction of mitochondrial outer membrane permeabilization (MOMP).