Mitochondrial reactive oxygen species (ROS) in animal cells: relevance to aging and normal physiology

Abstract

In animal mitochondria, the four electron reduction of molecular oxygen to produce water at respiratory complex IV is the terminal step in substrate oxidation. However, respiratory complexes I, II, and III can participate in the single electron reduction of oxygen to produce the radical species superoxide. This progenitor reactive oxygen species (ROS) participates in a number of reactions that generate other ROS. These molecules may react with, and damage, intracellular macromolecules, leading to cellular dysfunction. Mitochondrial ROS production is often considered from this perspective of macromolecular damage and is central to the “oxidative damage theory of aging”, which suggests the accumulation of oxidative damage in animal cells underlies the aging phenotype and limits lifespan. In this review, we discuss some experimental results accumulated over the past decade that are inconsistent with this theory. A limitation of the theory is that it presupposes mitochondrial ROS are inherently harmful. However, it is increasingly apparent that some basic cellular functions are physiologically regulated by normal levels of mitochondrial ROS. For example, cell growth and division, the apoptotic pathway, and mitochondrial fusion–fission dynamics all appear to be redox-regulated by mitochondrial ROS and perhaps the matrix manganese superoxide dismutase (MnSOD). Therefore, it is less clear how the balance between ROS regulation of normal cellular activities and ROS-mediated macromolecular damage is maintained and how this relates to aging and longevity in animals.