Redox dynamics of manganese as a mitochondrial life-death switch

Sten Orrenius, M.D., Ph.D., pioneered many areas of cellular and molecular toxicology and made seminal contributions to our knowledge of oxidative stress and glutathione (GSH) metabolism, organellar functions and Ca+2-dependent mechanisms of cell death, and mechanisms of apoptosis. On the occasion of his 80th birthday, we summarize current knowledge on redox biology of manganese (Mn) and its role in mechanisms of cell death. Mn is found in all organisms and has critical roles in cell survival and death mechanisms by regulating Mn-containing enzymes such as manganese superoxide dismutase (SOD2) or affecting expression and activity of caspases. Occupational exposures to Mn cause “manganism”, a Parkinson's disease-like condition of neurotoxicity, and experimental studies show that Mn exposure leads to accumulation of Mn in the brain, especially in mitochondria, and neuronal cell death occurs with features of an apoptotic mechanism. Interesting questions are why a ubiquitous metal that is essential for mitochondrial function would accumulate to excessive levels, cause increased H2O2 production and lead to cell death. Is this due to the interactions of Mn with other essential metals, such as iron, or with toxic metals, such as cadmium? Why is the Mn loading in the human brain so variable, and why is there such a narrow window between dietary adequacy and toxicity? Are non-neuronal tissues similarly vulnerable to insufficiency and excess, yet not characterized? We conclude that Mn is an important component of the redox interface between an organism and its environment and warrants detailed studies to understand the role of Mn as a mitochondrial life-death switch.