Matrix cadmium accumulation depolarizes mitochondria isolated from mouse brain

Cadmium (Cd2+) is an environmental contaminant commonly found in industrial settings with a biological half-life of 30 years. Although the accumulation and subsequent cytotoxicity of Cd2+ in nervous tissue is well documented, it is unclear exactly how Cd2+ kills cells. One potential mechanism involves inhibition of cellular energy production. In this study, we used fluorescence microscopy to monitor the effects of Cd2+ on mitochondrial membrane potential (ΔΨm) in individual mitochondria isolated from mouse brain. Mitochondria were attached to microscopy glass and loaded with rhodamine 123, a fluorescent indicator that collects in energized and respiring mitochondria, i.e., those with a robust ΔΨm. We found that Cd2+ at relatively low concentrations quickly and completely abolished ΔΨm. Cd2+ actions were concentration- dependent, and were relatively potent and efficacious when compared to calcium (Ca2+) and zinc (Zn2+). Moreover, the Ca2+ uniporter blocker ruthenium red protected against Cd2+-induced depolarization, suggesting that matrix entry of Cd2+ through this traditional Ca2+ pathway is necessary for its effect. These results demonstrate that Cd2+ substantially inhibits mitochondrial function and provide important insight regarding the mechanism of Cd2+-mediated neurotoxicity.