Mitochondrial Transplantation as a Therapeutic Strategy: From Energy Replacement to Metabolic and Immune...

Mitochondrial dysfunction drives diseases, including ischemia-reperfusion injury, neurodegenerative disorders, cardiovascular disease, metabolic syndrome, and inflammation. Conventional mitochondria-targeted strategies offer only partial rescue and are insufficient for severe, irreversible damage. Mitochondrial transplantation (MT)-the delivery of exogenously isolated functional mitochondria to injured cells-has emerged as a promising therapeutic strategy that directly restores mitochondrial bioenergetic function and may subsequently modify the tissue microenvironment. This Review examines the entire MT pipeline, from mitochondrial source selection, isolation and preservation, to in vivo delivery strategies. We critically examine the multiple mechanisms underlying MT's therapeutic efficacy, including cellular uptake and intracellular integration, energy restoration and metabolic reprogramming, redox rebalancing, remodeling of mitochondrial quality control (fusion/fission, mitophagy, biogenesis), and immunomodulation. We summarize preclinical and clinical applications across multiple organ systems-heart, nervous system, liver, kidney, lung, skeletal muscle, retina-as well as in oncology and aging. We analyze five major translational bottlenecks: the lack of standardized manufacturing protocols, undefined dose-response relationships, immunogenicity and long-term safety uncertainties, the decisive impact of mitochondrial heterogeneity, and regulatory ambiguity. We outline future directions-mechanistic deepening, engineered target delivery, individualized mitochondrial medicine, combinatorial regimens, and a phased clinical roadmap. MT is not merely energy supplementation; it may reshape cellular metabolism, quality control networks, and immune microenvironments, representing a shift from pharmacological modulation of mitochondrial function toward organelle replacement strategies. Despite challenges, these advances may facilitate individualized mitochondrial therapies as a proposed future direction.