Context-Dependent Functional Outcomes of Mitochondrial Transfer: A Donor-Recipient Perspective

Intercellular mitochondrial transfer has emerged as a fundamental mechanism regulating tissue homeostasis and disease progression, yet its complex regulatory network remains incompletely understood. This review synthesizes the principal transfer mechanisms, focusing on tunneling nanotube (TNT)-mediated direct contact and extracellular vesicle (EV)-mediated indirect transport. Based on the functional disparity between donor and recipient cells, we categorize four prototypical pairing modes and delineate the functional diversity of mitochondrial transfer in metabolic support, tissue repair, and stress responses. Building on this framework, we propose five key determinants as the core dimensions for understanding transfer efficiency and functional outcomes across various contexts: donor mitochondrial quality, donor transfer capacity, recipient metabolic demand, recipient integration capacity, and donor-recipient compatibility. Integrating these factors provides a conceptual basis for explaining the dual effects of mitochondrial transfer-supporting tissue regeneration and functional recovery while, in certain microenvironments, driving pathological reprogramming. This review offers a comprehensive framework for mechanistic studies and clinical translation of mitochondrial transfer and highlights its therapeutic potential in regenerative medicine, aging intervention, and cancer therapy.