Calcium and Mitochondrial Reactive Oxygen Species Generation: How to Read the Facts

A number of recent discoveries indicate that abnormal Ca²⁺ signaling, oxidative stress, and mitochondrial dysfunction are involved in the neuronal damage in Alzheimer's disease. However, the literature on the interactions between these factors is controversial especially in the interpretation of the cause-effect relationship between mitochondrial damage induced by Ca²⁺ overload and the production of reactive oxygen species (ROS). In this review, we survey the experimental observations on the Ca²⁺-induced mitochondrial ROS production, explain the sources of controversy in interpreting these results, and discuss the different molecular mechanisms underlying the effect of Ca²⁺ on the ROS emission by brain mitochondria.