Mobile Powerhouses: Mitochondria Transfer via Tunnelling Nanotubes in Brain Health and Neurodegenerative Diseases

TL;DR

Mitochondria can move between brain cells through structures called tunnelling nanotubes, which may help with energy balance but also spread disease.

Contribution

This paper highlights how tunnelling nanotubes mediate mitochondrial transfer in the brain and its implications for health and disease.

Findings

Mitochondria transfer via tunnelling nanotubes supports bioenergetic recovery and immune modulation in the brain.

Glial cells transfer mitochondria to stressed neurons, aiding in quality control and metabolic balance.

TNT-mediated transfer can also spread pathological proteins and support tumor growth.

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.

Within the brain microenvironment, mitochondria are preferentially transferred from glial cells to metabolically stressed neurons via tunnelling nanotubes (TNTs). This intercellular exchange restores bioenergetic homeostasis and contributes to mitochondrial quality control through transmitophagy. In contrast, malignant cells can hijack TNT‐mediated mitochondrial transfer to fuel metabolic reprogramming, promote tumour growth and drive chemoresistance.

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