Oxidative stress and mitochondrial oxidative damage have been implicated in the etiology of numerous common diseases such as degenerative diseases, diabetes, obesity and aging. Mitochondrial respiratory chain is a major source of superoxide and derived reactive oxygen species (ROS) in vivo. Oxidative stress results from over production of ROS, often leading to peroxidation of membrane phospholipids and production of reactive aldehydes, particularly 4-hydroxy-2-nonenal (HNE). There is strong evidence that mild uncoupling of oxidative phosphorylation attenuates mitochondrial ROS production and protects against cellular damage. HNE induces mitochondrial uncoupling by specific and inhibitable interactions with the uncoupling proteins UCP1, UCP2 and UCP3, and with the adenine nucleotide translocase (ANT). These proteins are members of a large family of at least 35 anion carriers present in the mitochondrial inner membrane. This suggests a physiological role for HNE and/or other lipid peroxidation products in a negative feed-back loop mechanism which acts to prevent excessive mitochondrial ROS production and thus protects against the effects of oxidative stress.