Mitochondrial Transfer Between Cells: Physiological Roles and Therapeutic Potential

Mitochondria were long regarded as strictly intracellular organelles, inherited only vertically and confined within the cytoplasm of a single cell. That assumption no longer holds. Over the last two decades, a growing body of work has shown that mitochondria, and fragments of their genome, move between cells through tunneling nanotubes, gap junctions, extracellular vesicles, and even as free organelles ejected into the extracellular space — a phenomenon now termed horizontal mitochondrial transfer (HMT). This review synthesizes the physiological logic of HMT and evaluates the translational progress of artificial mitochondrial transplantation (MTT). A structured narrative review was conducted of peer-reviewed literature indexed and supplemented by hand-searching of reference lists, focusing on molecular mechanisms of HMT, in vivo and in vitro transplantation models, and extracellular-vesicle biology, following a reproducible, informed search and eligibility strategy. Contact-dependent transfer relies on Miro1/2-TRAK-KIF5-driven trafficking along tunneling nanotubes and on connexin-43 gap junctions, while contact-independent transfer is carried out chiefly by extracellular vesicles — exosomes, microvesicles, exophers, and migrasomes — each with distinct cargo and destination. Preclinical models across cardiac, cerebral, renal, and musculoskeletal injury consistently show that exogenous mitochondria restore bioenergetics and reduce apoptosis, and early-phase clinical experience in pediatric cardiac surgery and stroke supports feasibility and safety. HMT is not a laboratory curiosity but a conserved physiological communication system that, once dysregulated, can be hijacked by tumors and, once harnessed deliberately, offers a genuinely novel therapeutic modality. Its clinical maturation will depend on resolving questions of mitonuclear compatibility, immunogenicity, and manufacturing scale.