Abstract
Mitochondria are central regulators of cellular metabolism, calcium homeostasis and survival. Owing to the brain's exceptional energy demand, mitochondrial dysfunction is tightly linked to neurodegenerative and neuroinflammatory disorders. Recent evidence challenges the traditional view of mitochondria as strictly cell-autonomous organelles, revealing that they can be exchanged between cells via intercellular transfer by extracellular vesicles, gap junctions or tunnelling nanotubes (TNTs) as part of an adaptive mechanism of metabolic support and signalling. Among the pathways mediating this intercellular exchange, TNTs-thin, actin-rich cytoplasmic bridges-have emerged as key conduits for mitochondrial transfer in the nervous system. TNTs enable bidirectional exchange of mitochondria between neurons, glia and vascular cells, thereby promoting bioenergetic recovery after injury and modulating immune and inflammatory responses. This review summarizes current evidence for TNT-mediated mitochondrial transfer in the brain and highlights the underlying molecular mechanisms that coordinate mitochondrial movement, including cytoskeletal dynamics, mitochondrial trafficking machinery and stress-induced signalling cascades. While mitochondrial donation can restore metabolic balance and promote neuroprotection, it may also facilitate the spread of pathological proteins, contributing to disease progression. Understanding the underlying molecular mechanism of TNT-mediated mitochondrial transfer provides a new framework for exploring metabolic communication and cellular resilience in the brain. By emphasizing emerging conceptual and mechanistic insights, we outline how advancing this field could pave the way for the development of innovative therapeutic strategies for neurodegenerative and neuroinflammatory disorders.