Vanadium compounds induced mitochondria permeability transition pore (PTP) opening related to oxidative stress

Vanadium compounds have been regarded as promising in therapeutic treatment of diabetes and in cancer prevention. In the present work, we studied the effects of vanadium compounds on mitochondria to investigate the mechanisms of toxicity. Mitochondria were isolated from rat liver and incubated with a variety of vanadium compounds, i.e. VOSO4, NaVO3, and vanadyl complexes with organic ligands. Our studies indicated that VO2+, VO3-, VO(acac)2 and VOcit (1–100 μM) could induce mitochondrial swelling in a concentration dependent manner and disrupt mitochondrial membrane potential (Δψm) in a time dependent manner, which is quite different from the rapid Δψm collapse caused by Ca2+ or CCCP (carbonyl cyanide m-chlorophenylhydrazone, a mitochondrial uncoupling reagent). Release of cytochrome c (Cyt c) was observed and could be inhibited by cyclosporin A (CsA), an inhibitor of the mitochondrial permeability transition pore (PTP). Interestingly, VOdipic caused release of Cyt c without mitochondrial swelling and Δψm disruption, an action previously only observed on the Bax protein, suggesting a potentially role of VOdipic in regulating PTP opening. In addition, all the vanadium compounds tested stimulated mitochondrial production of reactive oxygen species (ROS). Antioxidants, i.e. vitamin C and E, significantly delayed the Δψm disruption. Overall, our experimental evidence indicated vanadium compounds exhibited multiple actions on mitochondria. Vanadium compounds did induce oxidative stress on mitochondrial and thus caused PTP opening, which led to collapse of Δψm and Cyt c release as the initiation of cell apoptosis.