Why does reperfusion injury result in increased production of reactive oxygen species (ROS) from damaged mitochondria?

From the Guidelines

Reperfusion injury results in more reactive oxygen species (ROS) from damaged mitochondria due to the sudden restoration of oxygen to previously ischemic tissues, leading to electron leakage and increased ROS production, as supported by the most recent study in 2019 1. When blood flow returns to previously ischemic tissues, the damaged mitochondria cannot properly process the sudden influx of oxygen, leading to electron leakage and increased ROS production.

• The enzyme xanthine oxidase, which accumulates during ischemia, rapidly generates ROS when oxygen returns, contributing to the increased ROS production.
• The mitochondria also experience calcium overload during reperfusion, further disrupting their membranes and increasing ROS production.
• The combination of these factors—damaged electron transport components, xanthine oxidase activity, and calcium overload—creates a "perfect storm" for excessive ROS generation that overwhelms cellular antioxidant defenses and leads to oxidative damage of cellular components, perpetuating the injury cycle, as described in the study published in Redox Biology in 2018 1. The production of ROS is a major contributor to the pathogenesis of reperfusion injury, and understanding the mechanisms underlying this process is crucial for the development of effective therapeutic strategies, as highlighted in the study published in Circulation in 2019 1.
• The study suggests that supranormal systemic arterial oxygen concentrations during reperfusion after cardiac arrest may exacerbate free radical–mediated neurological injury and protein disruption, and may worsen neurological outcome.
• Therefore, it is essential to carefully manage oxygen levels during reperfusion to minimize the production of ROS and mitigate the damage caused by reperfusion injury.

From the Research

Mechanisms of Reperfusion Injury and Reactive Oxygen Species Production

• Reperfusion injury results in the production of reactive oxygen species (ROS) from damaged mitochondria due to the restoration of blood flow and oxygenation to ischemic tissues 2, 3.
• The production of ROS during ischemia-reperfusion injury is not a non-specific consequence of oxygen interacting with dysfunctional mitochondria, but rather occurs through a defined mechanism 4.
• Mitochondria play a critical role in reperfusion injury by producing excessive ROS, which damages cellular components and initiates cell death 5.

Role of Mitochondrial Membrane Potential in ROS Generation

• The mitochondrial membrane potential plays a pivotal role in ROS generation during reperfusion, with hyperactive oxidative phosphorylation generating high mitochondrial membrane potentials that produce excessive ROS 5.
• Posttranslational modifications of key oxidative phosphorylation proteins caused by ischemia induce a hyperactive state upon reintroduction of oxygen, leading to a "burst" of ROS upon reperfusion 5.

Mitochondrial Dysfunction and ROS Production

• Mitochondrial dysfunction is involved in various organs and tissues in ischemia-reperfusion injury, with excessive free radicals inducing mitochondrial damage and disorder of mitochondrial fusion and fission resulting in further reduction of mitochondrial number and function 6.
• Mitochondrial oxidative stress, mitochondrial fission, and mitochondrial membrane permeable transport pore formation are all involved in the pathogenesis of liver ischemia-reperfusion injury, with corresponding protective measures aiming to inhibit or slow the damage 6.