Mitochondria and Reactive Oxygen Species

Fascination by the mitochondria, “the colonial posterity of migrant prokaryocytes, probably primitive bacteria that swam into ancestral precursors of our eukaryotic cells and stayed there,”1 stems from the above-mentioned nebulous endosymbiotic theory of their origin, as well as from the growing realization of a very special role that they play in the pathogenesis of diverse diseases. These organelles generate energy primarily in the form of the electrochemical proton gradient (H), which fuels ATP production, ion transport, and metabolism.2 Generation of this universal energy currency, H, occurs through the series of oxidative reactions conducted by the respiratory chain complexes at the ion-impermeable, almost cholesterolfree inner membrane. Reduced nicotinamide adenine dinucleotide represents the entry point to the complex I (reduced nicotinamide adenine dinucleotide:ubiquinone reductase), whereas the reduced ubiquinol enters the respiratory chain in the complex III (ubiquinol:cytochrome c [cyt-c] reductase) to reduce cyt-c, the electron carrier to the complex IV, cyt-c oxidase. Each of these steps generates H by electrogenic pumping of protons from the mitochondrial matrix to the intermembrane space and is coupled to electron flow, thus generating the electric membrane potential of 180 to 220 mV and a pH gradient of 0.4 to 0.6 U across the inner mitochondrial membrane resulting in the negatively charged matrix side of the membrane and alkaline matrix. Ultimately, accumulated H is converted into the influx of protons into the matrix driving ATP synthesis or protein transport. In addition, these end points are necessary for the execution of 2 major enzymatic metabolic pathways within the mitochondrial matrix: the tricarboxylic acid (TCA) oxidation cycle and the fatty acid -oxidation pathway. This intricate system fueling cellular functions is as elegant as it is vulnerable: practically every component of the system, from the electron transport chain complexes to the permeability properties of the membranes, is a target for various noxious stimuli, some of which can be generated within mitochondria themselves. The list of these noxious stimuli is too long to be recounted here, and the interested reader may refer to a recent excellent review.3 These ancestral oxygen-using proteobacterial invaders carried with them into eukaryotic cells not only evolutionary benefits but also potential side reactions, most dangerous of which are “exothermic oxygen combustion and free radical emission.” This review is focused on one component of the noxious mitochondrial pathway: reactive oxygen species (ROS) from a mitochondrial perspective, which has previously been extensively reviewed.4 Therefore, we shall present the most recent findings but periodically offer historical perspective.