Mitochondrial transplantation in ischaemia–reperfusion injury: progress and challenges in clinical translation

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Timely restoration of blood flow is essential to salvage ischaemic tissues and donor organs, but reperfusion may itself cause ischaemia–reperfusion injury (IRI), limiting recovery after coronary or cerebral revascularisation, organ transplantation, major surgery, or trauma resuscitation. Mitochondrial dysfunction is a central component of IRI and provides a rationale for delivering functional exogenous mitochondria to restore cellular bioenergetics and modulate injury responses. This strategy has recently been evaluated in multiple IRI models. We synthesise evidence from cellular, isolated-organ, animal, and patient studies and evaluate mitochondrial preparation, functional potency, organ exposure, cellular uptake, mechanisms of action, and safety. Cross-organ evidence indicates that the biological effects of mitochondrial transplantation depend on the functional state of the mitochondrial material and effective target-organ exposure; neither particle count, protein content, nor tissue-level tracer signals alone adequately predict these effects. In studies with material-state controls, mitochondria retaining membrane integrity and respiratory function improved energy metabolism, reduced tissue injury, and improved some short-term functional measures, whereas inactivated or damaged preparations did not reproduce these effects. Mechanistic studies suggest that exogenous mitochondria can alter cellular bioenergetics and endogenous mitochondrial networks. They may also influence local tissue responses before widespread cellular uptake or undergo processing by tissue-resident immune cells. Mitochondrial source, preparation and storage, administered load, and delivery route further influence functional potency, organ exposure, and safety. One study of high-load, non-targeted administration observed increased inflammation and mortality, indicating that tissue detection cannot substitute for assessments of efficacy and safety. Machine perfusion provides a controlled platform for delivery, measurement of organ exposure, and preimplantation assessment of organ function. Existing patient studies have been small and mainly support procedural feasibility, short-term safety observations, and preliminary functional signals. Current evidence supports biological effects of functional exogenous mitochondria across multiple IRI models, but clinical efficacy has not been reproducibly demonstrated in controlled studies. Future studies should integrate traceable preparation, batch-level functional potency, actual organ exposure, and route-specific safety within a unified validation framework and use controlled clinical trials to define effective doses, appropriate clinical settings, and patient benefit.