MITOCHONDRIAL-MEMBRANE POTENTIAL (DELTA-PSI(MT)) IN THE COORDINATION OF P53-INDEPENDENT PROLIFERATION AND APOPTOSIS PATHWAYS IN HUMAN COLONIC-CARCINOMA CELLS

We have previously defined depressed mitochondrial function as a deter minant in colon cancer risk and progression and established that metab olism of butyrate, a short-chain fatty acid generated during the ferme ntation of fiber by endogenous intestinal bacteria, induces mitochondr ial function-dependent growth arrest and apoptosis of colonic carcinom a cells in vitro. Here, we dissect the relationships among mitochondri al function, growth arrest, and apoptosis, reporting that initiation a nd maintenance of butyrate-mediated p53-independent p21(WAF1/Cip1) ind uction and subsequent G(0)/G(1) arrest require an intact mitochondrial membrane potential (Delta Psi(mt)) and that the process of dissipatio n of the Delta Psi(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 tiss ues, such as the colonic mucosa.