The intrinsic mitochondrial membrane potential (δψ_m) is associated with steady-state mitochondrial activity and the extent to which colonic epithelial cells undergo butyrate-mediated growth arrest and apoptosis

Transformation of colonic epithelial cells is characterized by decreased mitochondrial activity, increased mitochondrial membrane potential (Δψ_m), and disruptions in the equilibrium between cell proliferation and death by apoptosis. We have previously shown that an intact Δψ_m is essential for growth arrest and apoptosis induced by butyrate, a physiological regulator of maturation in these cells, suggesting a role for the Δψ_m in the initiation and integration of proliferation and apoptotic pathways. To extend this work, we have generated isogenic cell lines, from SW620 human colonic carcinoma cells, which exhibit significant differences in intrinsic Δψ_m. These differences in Δψ_m are not linked to alterations in viability, Bcl-2 levels, or the differentiation status of the cells. However, compared with parental cells and those with increased Δψ_m, cells with decreased intrinsic Δψ_m exhibit significantly higher levels of steady-state mitochondrial mRNA and butyrate-induced p21 ^WAF1/Cip1 and G₀-G₁ arrest. Moreover, despite butyrate-mediated translocation of proapoptotic Bax and Bak to the mitochondria, fewer cells with elevated intrinsic Δψ_m exhibit concomitant cytochrome c release, and cells with elevated Δψ _m undergo significantly lower levels of Δψ_m. dissipation and apoptosis than parental cells, or cells with decreased Δψ_m. Homeostasis of the colonic mucosa depends on balancing cell proliferation with apoptosis, and mitochondrial abnormalities are associated with disruptions in this balance. Thus, by affecting steady-state mitochondrial activity and the extent to which cells enter growth arrest and apoptotic cascades, these data establish a role for the intrinsic Δψ_m in contributing to the probability of colonic tumorigenesis and progression.