Mitochondrial transfer technologies with molecular insights into clinical applications

Mitochondria are essential cell signaling, survival, and bioenergetic organelles that uniquely harbor a maternally inherited, multicopy genome called mitochondrial DNA (mtDNA). The occurrence or accumulation of mtDNA mutations underlies a spectrum of inherited and acquired mitochondrial syndromes and diseases and is increasingly recognized as a source of metabolic plasticity, clonal fitness, and therapy tolerance in cancer. Recent studies have revealed mitochondrial transfer as a potential mode of intercellular communication that could compensate for mtDNA mutation-associated mitochondrial dysfunction. Transfer of mitochondria can restore homeostasis in stressed recipient cells by rebuilding respiratory capacity, rebalancing redox state, and reshaping cell fate. Reported mechanisms of transfer include tunneling nanotubes, extracellular vesicles, cell fusion, and others, such as macropinocytosis. Here, we review and evaluate emerging technologies developed for mitochondrial transfer studies and define the impact of transfer on cell physiology and pathology. We discuss translational opportunities for mitochondrial transfer-based interventions, as well as how mitochondrial exchange may represent a new framework for understanding tumor heterogeneity, adaptation, and aggressiveness.