A cellular state-gated model for the biogenesis and function of mitochondrial extracellular vesicles

Intercellular communication is fundamental to multicellular life, orchestrating development, homeostasis, and disease progression, yet the principles governing biogenesis and functional specialization of extracellular vesicles (EVs) remain intensely debated. Specifically, a mechanistic framework reconciling the profound heterogeneity and context-dependent functions of mitochondria-derived EVs (MitoEVs) is notably absent. This review introduces a novel conceptual framework: the "Cellular State-Gated Model", positing that MitoEVs biogenesis and function are not linear pathways but are dynamically regulated by the overarching state of the cell. We first deconstruct the diverse secretion mechanisms, including ESCRT(Endosomal Sorting Complex Required for Transport)-dependent pathways, membrane-budding events, and apoptosis-associated routes. We then propose a new classification paradigm for MitoEVs and critically evaluate current methods for their isolation and characterization. Subsequently, we explore the functional dichotomy of MitoEVs in both health and disease, and the untapped potential of MitoEVs as both therapeutic targets or delivery vehicles. This model provides a roadmap to understand how cells translate internal state into specific intercellular signals, offering a new lens for future research and therapeutic innovation in the field.