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Endogenous mitochondrial transfer can occur through tunneling nanotubes, extracellular vesicles, cell fusion, gap junction\u2010associated communication, and phagocytosis\u2010like internalization. These routes differ substantially in distance, directionality, cargo integrity, regulatory control, and physiological relevance. Preclinical studies indicate that exogenous mitochondria may transiently improve bioenergetic function, attenuate oxidative stress, and support recovery in models of cardiac, skeletal muscle, and nervous system injury, whereas clinical evidence remains limited and heterogeneous. Broad clinical implementation remains constrained by unresolved biological and translational barriers. These include inefficient or poorly controlled uptake of extracellular mitochondria, uncertain long\u2010term persistence, incomplete functional integration, donor\u2010recipient incompatibility, mitochondrial\u2010nuclear mismatch, heteroplasmy\u2010related risks, immunogenicity, and the lack of standardized potency and delivery assays. Here, we critically synthesize the cellular mechanisms enabling mitoTT, emphasizing the checkpoints that determine whether transferred mitochondria are integrated, remodeled, immunologically sensed, or eliminated. We further discuss cristae biology and the mitochondrial contact site and cristae organizing system, mitochondrial nucleoid maintenance, mitochondrial DNA replication, organelle contact sites, and emerging bioengineering strategies required to move mitoTT from experimental rescue toward reproducible therapeutic application.<\/jats:p>","DOI":"10.1002\/advs.78137","type":"journal-article","created":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T05:02:56Z","timestamp":1791349376000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cellular Mechanisms Enabling Mitochondria Transfer and Transplantation"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2951-848X","authenticated-orcid":false,"given":"F. Seyma","family":"Gokdemir","sequence":"first","affiliation":[{"name":"Institute of Food, Agriculture and Livestock Development Baskent University  Ankara T\u00fcrkiye"},{"name":"Department of Food Processing, Kahramankazan Vocational School Baskent University  Ankara T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yagmur","family":"Ozendi","sequence":"additional","affiliation":[{"name":"Institute of Transplantation and Gene Sciences Baskent University  Ankara T\u00fcrkiye"},{"name":"Department of Exercise and Sport Sciences Faculty of Health Sciences Baskent University  Ankara T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3220-465X","authenticated-orcid":false,"given":"Gokhan Burcin","family":"Kubat","sequence":"additional","affiliation":[{"name":"Institute of Transplantation and Gene Sciences Baskent University  Ankara T\u00fcrkiye"},{"name":"Department of Exercise and Sport Sciences Faculty 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