How does electron leakage result in increased reactive oxygen species (ROS)?

From the Guidelines

Electron leakage in the mitochondrial electron transport chain results in increased reactive oxygen species (ROS) production when electrons prematurely escape from the transport chain and directly react with oxygen molecules, primarily at Complexes I and III, as supported by the study published in Cell Death and Differentiation in 2018 1. This process occurs when electrons leak out of the transport chain before reaching Complex IV, where they would normally reduce oxygen to water. Instead, these leaked electrons partially reduce oxygen to form superoxide (O2•-), the precursor to other ROS. The study highlights that mitochondria-derived O− is rapidly converted to H2O2 by superoxide dismutase (SOD2/MnSOD in the mitochondrial matrix; SOD1 in the inter-membrane space and cytoplasm) 1. Some key points to consider include:

• The primary sources of mitochondrial O−2 are Complexes I and III, and TCA cycle enzymes, as noted in the study 1.
• Increased respiration and a hyperpolarised mitochondrial membrane can increase ROS production in neurons, while inhibition of the respiratory complexes can also increase ROS production when the mitochondrial membrane potential is maintained by reverse activity of the F F o1 ATP synthase and ROS are generated through electron leaks 1.
• The levels of steady-state mitochondrial ROS depend not only on ROS generation but are strongly regulated by respiration, with underlying factors disrupting respiration likely determining the ROS response 1. The superoxide radical can then be converted to hydrogen peroxide by superoxide dismutase, and further to hydroxyl radicals through Fenton reactions, as described in the study 1. These ROS can damage cellular components, including proteins, lipids, and DNA, contributing to oxidative stress and potentially leading to cell dysfunction or death if antioxidant defenses are overwhelmed.

From the Research

Electron Leakage and Reactive Oxygen Species

• Electron leakage during biologic oxidations is a mechanism by which reactive oxygen species (ROS) are produced 2
• This leakage occurs when electrons escape from the mitochondrial respiratory chain and react with oxygen, resulting in the formation of superoxide anion, a type of ROS 3
• The superoxide anion can then be converted to hydrogen peroxide, which can be further converted to harmless water by catalase, or it can react with other molecules to form more harmful ROS 3

Mitochondrial Membrane Potential and ROS Formation

• The mitochondrial membrane potential plays a role in the rate of ROS formation, with changes in the membrane potential affecting the magnitude and direction of ROS production 3
• The metabolic state of the mitochondria also influences ROS production, with different metabolic states resulting in varying levels of ROS formation 3

Consequences of Increased ROS Production

• Increased production of ROS can lead to oxidative stress, causing damage to cellular components such as proteins, lipids, and DNA 4, 5
• Oxidative stress has been implicated in various diseases, including neoplastic, cardiovascular, and neurodegenerative diseases 2
• Mitochondrial dysfunction, resulting from ROS-induced damage, can contribute to the development of these diseases 5

Mitochondrial Metabolism of ROS

• Mitochondria have evolved mechanisms to protect against cellular oxidative damage, including the scavenging of ROS produced by other cellular sources 5
• The elimination of old, dysfunctional mitochondria, which are characterized by high susceptibility to oxidative damage, can help to attenuate mitochondrial dysfunction 5