Fig. 3 |. Mitochondrial priming of myofibroblasts.

Mitochondrial priming refers to the proximity of mitochondria to the apoptosis threshold and is determined by the relative expression of pro-apoptotic (effectors, activators and sensitizers) and pro-survival members of the BCL-2 family of proteins. ‘Unprimed’ fibroblasts express low amounts of activators and/or effectors, leading to an apoptosis-resistant phenotype. Conversely, high expression of sensitizers, activators and/or effectors results in high mitochondrial priming, ultimately triggering cytochrome-c-mediated mitochondrial outer membrane permeabilization and apoptosis. However, myofibroblasts can survive with high mitochondrial priming if a pro-survival mechanism is activated. In this cellular state, known as ‘primed for death’, cells are poised to die and become dependent on one or more pro-survival proteins to sequester pro-apoptotic proteins and ensure survival. BCL-2 homology domain 3 (BH3) mimetic drugs can trigger the intrinsic pathway of apoptosis in primed-for-death myofibroblasts by binding to pro-survival proteins, resulting in the release of activator proteins, which can then bind to and activate effector proteins.