During the last three decades, 4-hydroxy-2-nonenal (HNE), a major a,b-unsaturated aldehyde product of n-6 fatty acid oxidation, has been shown to be involved in a great number of pathologies such as metabolic diseases, neurodegenerative diseases and cancers. These multiple pathologies can be explained by the fact that HNE is a potent modulator of numerous cell processes such as oxidative stress signaling, cell proliferation, transformation or cell death. The main objective of this review is to focus on the different aspects of HNE-induced cell death, with a particular emphasis on apoptosis. HNE is a special apoptotic inducer because of its abilities to form protein adducts and to propagate oxidative stress. It can stimulate intrinsic and extrinsic apoptotic pathways and interact with typical actors such as tumor protein 53, JNK, Fas or mitochondrial regulators. At the same time, due to its oxidant status, it can also induce some cellular defense mechanisms against oxidative stress, thus being involved in its own detoxification. These processes in turn limit the apoptotic potential of HNE. These dualities can imbalance cell fate, either toward cell death or toward survival, depending on the cell type, the metabolic state and the ability to detoxify.

Intracellular pH (pH i ) has an important role in the maintenance of normal cell function, and hence this parameter has to be tightly controlled within a narrow range, largely through the activity of transporters located at the plasma membrane. These transporters can be modulated by endogenous or exogenous molecules as well as, in some pathological situations, leading to pH i changes that have been implicated in both cell proliferation and cell death. Whereas intracellular alkalinization seems to be a common feature of proliferative processes, the precise role of pH i in apoptosis is still unclear. The present review gathers the most recent advances along with previous data on both the origin and the role of pH i alterations in apoptosis and highlights the major concerns that merit further research in the future. Special attention is given to the possible role played by pH i -regulating transporters.