How does the electron transport chain produce reactive oxygen species (ROS)?

From the Guidelines

The electron transport chain produces reactive oxygen species (ROS) primarily through the leakage of electrons during cellular respiration, particularly at Complexes I and III, and TCA cycle enzymes, as electrons react with molecular oxygen to form superoxide (O2−) 1. This process occurs when electrons prematurely escape from the electron carriers in the mitochondrial inner membrane and react with molecular oxygen.

• The primary sources of mitochondrial O2− are Complexes I and III, and TCA cycle enzymes 1.
• The assembly of Complex I into supercomplexes can dictate the rate of ROS formation 1.
• Increased respiration and a hyperpolarised mitochondrial membrane can increase ROS production in neurons 1.
• Conversely, inhibition of the respiratory complexes can also increase ROS production 1, when the mitochondrial membrane potential may be maintained by reverse activity of the F F o1 ATP synthase and ROS are generated through electron leaks. The production of ROS is strongly regulated by respiration, with the underlying factors disrupting respiration likely determining the ROS response 1.
• Once superoxide is formed, it can be converted to hydrogen peroxide by superoxide dismutase, and potentially to the highly reactive hydroxyl radical through the Fenton reaction.
• While ROS production is a natural byproduct of cellular respiration, excessive ROS generation can damage cellular components including proteins, lipids, and DNA, contributing to oxidative stress and various pathological conditions, such as ageing and neurodegeneration 1.

From the Research

Electron Transport Chain and Reactive Oxygen Species Production

The electron transport chain (ETC) is a crucial process in mitochondria that generates ATP through oxidative phosphorylation. However, it also produces reactive oxygen species (ROS) as a byproduct.

• The ETC consists of four multiprotein complexes (I-IV) and two electron transporters, ubiquinone and cytochrome c 2.
• The electron flow in the ETC is coupled with the generation of a proton gradient across the inner membrane, which is used by complex V (ATP synthase) to produce ATP 2.
• Some electrons are directly transferred to O2, resulting in the generation of ROS in the ETC 2, 3.

Sites of ROS Generation in the ETC

Research has identified specific sites in the ETC where ROS are generated:

• Site IF and IQ in complex I 2
• Site IIF in complex II 2
• Site IIIQo in complex III 2
• The flavin mononucleotide group (FMN) of complex I is also a major site of ROS generation, particularly through reversed electron transfer supported by the complex II substrate succinate 3.

Physiological and Pathological Regulation of ROS

ROS play a significant role in cell physiology and pathology:

• They act as signaling molecules, involved in cell proliferation, hypoxia adaptation, and cell fate determination 2.
• Excessive ROS can cause irreversible cell damage and even cell death, contributing to the development of various diseases 2, 4.
• Proton leak and uncoupling proteins (UCPs) help regulate ROS production and mitigate oxidative stress 2.