Therapeutic strategies to ameliorate mitochondrial oxidative stress in ischaemia-reperfusion injury: A narrative review

Abstract

Mitochondrial reactive oxygen species (mROS) play a crucial physiological role in intracellular signalling. However, high levels of ROS can overwhelm antioxidant defences and lead to detrimental modifications in protein, lipid and DNA structure and function. Ischaemia-reperfusion injury is a multifaceted pathological state characterised by excessive production of mROS. There is a significant clinical need for therapies mitigating mitochondrial oxidative stress. To date, a variety of strategies have been investigated, ranging from enhancing antioxidant reserve capacity to metabolism reduction. While success has been achieved in non-clinical models, no intervention has yet successfully transitioned into routine clinical practice. In this article, we explore the different strategies investigated and discuss the possible reasons for the lack of translation.

Keywords: antioxidant; ischaemia-reperfusion injury; mROS; mitochondria; oxidative stress.

Figure 1. Publications by year related to ischaemia-reperfusion injury.

The search on this database (with data extraction) was conducted on December 22, 2024. IRI, ischaemia-reperfusion injury,; ROS:, reactive oxygen species.

Figure 2. Mitochondrial physiology and mechanisms of mROS production in health.

During normal electron transport chain (ETC) flow, NADH and FADH₂ donate electrons to complexes I and II, respectively. Electrons pass down the chain with oxygen being the terminal electron acceptor at complex IV. In doing so, protons are pumped into the intermembrane space via complexes I, III and IV creating an electrochemical gradient. This energy gradient is used by complex V (ATP synthase) to phosphorylate adenosine diphosphate (ADP) to adenosine triphosphate (ATP), which is then used to fuel cellular metabolism. As electrons are carried through the ETC, a small fraction prematurely binds to oxygen, forming superoxide (O₂^•-). Red stars indicate the most common sources of mROS in health. Mitochondria have strong antioxidant systems that rapidly scavenge mROS to less potent ROS and then to water. CAT, catalase; e^-, electron; FMN, flavin mononucleotide; GPx, glutathione peroxidase; H₂O, water; H₂O₂, hydrogen peroxide; O₂, oxygen; Prx, peroxiredoxin; ROS, reactive oxygen species; SOD-2, superoxide dismutase-2; TRx, thioredoxin; TRxR, thioredoxin reductase; UQ, ubiquinone.

Figure 3. Mechanisms of mROS formation during ischaemia and reperfusion phases.

(A) Ischaemia phase. During hypoxia (ischaemia), electron flow down the electron transport chain (ETC) falls. Electrons accumulating at complex II lead to reverse electron flow towards complex I (indicated by red-dotted arrows) with increased ROS production and decreased ATP synthesis. Reduced electron flow also promotes ROS generation at complex III, particularly at the Q_i and Q_o sites within the Q cycle. These events cause the accumulation of mitochondrial metabolites, setting the stage for an ‘oxidative burst’ upon reperfusion/reoxygenation. (B) Reperfusion phase. Upon reoxygenation, the substrate-driven ETC resumes operation at high capacity, generating more ATP as well as more mitochondrial ROS (mROS). This also forces electrons to flow in reverse from complex II to complex I (again indicated by red-dotted arrows). Red stars mark common sources (complexes I and III) of mROS during reperfusion. The increase in mitochondrial oxidative stress triggers the opening of the mitochondrial permeability transition pore (mPTP) and release of cytochrome Cc (Cyt c), trigerring cell death pathways. e, electron; H₂O, water; O₂, oxygen; ROS, reactive oxygen species; UQ, ubiquinone.

Figure 4. Mitochondrial reactive oxygen species (mROS) production pathways during IRI and associated damage mechanisms.

ATP: adenosine triphosphate, Cyt c: cytochrome c, DAMPs: damage-associated molecular patterns, O₂: oxygen.