Intercellular Mitochondrial Transfer in Tauopathies: Mechanisms and Therapeutic Perspectives
We are pleased to announce that Dr. Amandine Grimm from the University of Basel, Swizerland, will join Targeting Mitochondria 2026 as a speaker.
Tauopathies are neurodegenerative diseases characterized by the abnormal accumulation and hyperphosphorylation of tau protein in neurons, leading to cognitive impairment. Notable examples include Alzheimer's disease (AD), frontotemporal dementia (FTD), and more than 20 other serious neurodegenerative diseases. A common feature of these disorders is mitochondrial dysfunction, which leads to bioenergetic deficits and contributes to neuronal cell death. Strikingly, abnormal tau has been shown to induce a wide range of defects in mitochondrial function, including in transport, dynamics, mitophagy, and bioenergetics.
Recent findings indicate that cells can exchange mitochondria through intercellular mitochondrial transfer (IMT), thereby supporting energy-deficient cells. In particular, studies have observed IMT between glia and neurons, and mitochondrial transfer has emerged as a key neuroprotective mechanism across a range of neurological conditions.
Therefore, we aimed to:
- Determine the impact of pathological tau on astrocyte-to-neuron mitochondrial transfer.
- Assess the therapeutic potential of mitochondrial transplantation in tau-induced bioenergetic defects.
We used SH-SY5Y cells expressing the P301L mutant tau, a mutation found in familial cases of frontotemporal lobar degeneration (FTLD), as an in vitro neuronal model of tauopathy, alongside A172 astrocytic cells. Key findings were confirmed in human iPSC-derived neurons and astrocytes.
We demonstrated that:
- IMT from astrocytes to neurons is significantly increased in the presence of P301L mutant tau.
- Contact-dependent transfer appears to be the dominant pathway, with an increased number of tunneling nanotubes observed between astrocytes and P301L-expressing neuronal cells.
- Transferred astrocytic mitochondria remain functional and improve cellular bioenergetics in recipient cells.
- The artificial transplantation of healthy astrocytic mitochondria increases bioenergetics and promotes neurite outgrowth in both control and P301L-expressing neuronal cells.
We provided the first evidence that disease-associated tau modulates IMT. The enhanced transfer observed in P301L-expressing neurons may reflect a compensatory mechanism to counteract mitochondrial dysfunction. Significantly, mitochondrial transplantation alleviated tau-induced defects in neuronal bioenergetics and morphology, supporting the development of cell-based mitochondrial therapies for neurodegenerative diseases.
