Mitochondrial Membrane Potential (ΔΨ_mt) in the Coordination of p53-independent Proliferation and Apoptosis Pathways in Human Colonic Carcinoma Cells¹

We have previously defined depressed mitochondrial function as a determinant in colon cancer risk and progression and established that metabolism of butyrate, a short-chain fatty acid generated during the fermentation of fiber by endogenous intestinal bacteria, induces mitochondrial function-dependent growth arrest and apoptosis of colonic carcinoma cells in vitro. Here, we dissect the relationships among mitochondrial function, growth arrest, and apoptosis, reporting that initiation and maintenance of butyrate-mediated p53-independent p21^WAF1/Cip1 induction and subsequent G₀/G₁ arrest require an intact mitochondrial membrane potential (ΔΨ_mt) and that the process of dissipation of the ΔΨ_mt is then essential for initiation of a butyrate-induced apoptotic cascade. Thus, we hypothesize that mitochondria play a pivotal role in coordinating proliferation and apoptosis pathways, a coordination that must be tightly regulated in rapidly renewing tissues, such as the colonic mucosa.