Histochem Cell Biol (2004) 122:395–412 DOI 10.1007/s00418-004-0676-y REVIEW Leni Moldovan · Nicanor I. Moldovan Oxygen free radicals and redox biology of organelles Accepted: 7 June 2004 / Published online: 25 September 2004  Springer-Verlag 2004 Abstract The presence and supposed roles of reactive oxygen species (ROS) were reported in literature in a myriad of instances. However, the breadth and depth of their involvement in cellular physiology and pathology, as well as their relationship to the redox environment can only be guessed from specialized reports. Whatever their circumstances of formation or consequences, ROS seem to be conspicuous components of intracellular milieu. We sought to verify this assertion, by collecting the available evidence derived from the most recent publications in the biomedical field. Unlike other reviews with similar ob- jectives, we centered our analysis on the subcellular compartments, namely on organelles, grouped according to their major functions. Thus, plasma membrane is a major source of ROS through NAD(P)H oxidases located on either side. Enzymes of the same class displaying low activity, as well as their components, are also present free in cytoplasm, regulating the actin cytoskeleton and cell motility. Mitochondria can be a major source of ROS, mainly in processes leading to apoptosis. The protein synthetic pathway (endoplasmic reticulum and Golgi ap- paratus), including the nucleus, as well as protein turn- over, are all exquisitely sensitive to ROS-related redox conditions. The same applies to the degradation pathways represented by lysosomes and peroxisomes. Therefore, ROS cannot be perceived anymore as a mere harmful consequence of external factors, or byproducts of altered cellular metabolism. This may explain why the indis- criminate use of anti-oxidants did not produce the ex- pected “beneficial” results in many medical applications attempted so far, underlying the need for a deeper ap- prehension of the biological roles of ROS, particularly in the context of the higher cellular order of organelles. Keywords Reactive oxygen species · Superoxide · NAD(P)H · Organelles · Actin cytoskeleton Introduction Overview Formation of reactive oxygen species (ROS), in particular of superoxide (O 2 · ), in many—if not all—cellular sys- tems is now beyond doubt, but their raison d’Þtre remains unclear. Proposed explanations for their occurrence range from accidental byproducts of aerobic metabolism, to highly regulated and sophisticated signaling mechanisms. These rationalizations depend on the specific type of re- action in which ROS are envisaged. However, no unitary view emerged so far to provide a satisfactory explanatory framework for the role of ROS in biology. A remarkable attempt, in this respect, was done by the late Manfred Saran who, in a posthumous hypothesis paper (Saran 2003), suggested that superoxide may be a universal cofactor of membrane functioning. Saran suggested that the ubiquitous and necessarily delocalized, weakly reac- tive, agent able to continuously alter the chemical and, not so surprisingly, the biomechanical stability of phospho- lipids, would be the NAD(P)H oxidase-derived O 2 · . This would also explain the continuous production of low levels of lipid peroxides, as part of the tighter controlled lipid- based signaling machinery of membranes (Roberts and Morrow 2002). This position could be considered at odds with those that view ROS as the “evil” mediators of oxi- dative stress (the list is long and therefore we will cite only one recent example: Sadek et al. 2003), and complements another hypothesis that links the stress and inflammatory responses and ageing to life-long oxidative damage to components of the cell (Lane 2003). As usual, the truth is probably at the crossroads of these hypotheses. Throughout the last decade, the role of ROS in con- trolling vital cellular processes became apparent, as nec- essary components in the normal functioning of cells (Aslan and Ozben 2003; Chiarugi 2003; Nathan 2003). L. Moldovan ( ) ) · N. I. Moldovan Davis Heart and Lung Research Institute, Room. 305D, The Ohio State University, 473 W 12th Avenue, Columbus, OH 43210, USA e-mail: moldovan-2@medctr.osu.edu Tel.: +1-614-2477645 Fax: +1-614-2477799