Compensatory Intercellular Mitochondrial Transfer Improves Bioenergetics in P301L Tau-Affected Neuronal Cells.

Overview

1. Cell Biology & Energy Metabolism, University Psychiatric Clinics (UPK) Basel, University of Basel, 4002 Basel, Switzerland; (A.R.); (A.B.)
2. Research Cluster Molecular and Cognitive Neurosciences, Department of Biomedicine, University of Basel, 4055 Basel, Switzerland
3. Neurobiology Laboratory for Brain Aging and Mental Health, University Psychiatric Clinics (UPK) Basel, University of Basel, 4002 Basel, Switzerland

Abstract

Highlights: What are the main findings? Intercellular mitochondrial transfer from astrocytes to neurons is significantly increased in the presence of P301L mutant tau. Contact-dependent transfer appears to be the dominant pathway of mitochondrial transfer, with an increased number of tunneling nanotubes between astrocytes and P301L-expressing neuronal cells. Abnormal tau protein does not significantly alter the intracellular fate of transferred mitochondria. Transferred astrocytic mitochondria remain functional and improve cellular bioenergetics in recipient cells.

What are the implications of the main findings? Our findings identified a novel protective mechanism supporting neuronal bioenergetics in tauopathies. Mitochondrial transfer may represent an attractive therapeutic strategy to compensate for energy deficits in neurodegeneration.

Abstract: Tauopathies are a group of neurodegenerative diseases characterized by the accumulation of abnormal tau protein, leading to mitochondrial dysfunction. Because of neurons’ high energy demands, such impairments significantly contribute to neuronal vulnerability. Recent evidence indicates that mitochondria can be transferred between cells to support energy-deficient cells through intercellular mitochondrial transfer (IMT). Given the impact of pathological tau on mitochondrial transport and cytoskeletal dynamics, we hypothesized that IMT is altered in tauopathies. We investigated IMT from astrocytes to neurons, as well as the influence of abnormal tau protein on this process, using co-cultures of SH-SY5Y cells (neuronal model) and A172 cells (astrocytic model). Key data were then confirmed in human iPSC-derived neurons and astrocytes. We show that IMT is enhanced in the presence of abnormal tau and occurs predominantly through contact-dependent mechanisms. Transferred mitochondria were either integrated into the host mitochondrial network, degraded in lysosomes, or remained isolated in the recipient cells’ cytosol. This transfer improved cellular respiration and was associated with increased bioenergetics in pathological cells. Together, our results highlight IMT as a link between tau pathology and neuronal metabolic adaptation, suggesting that this process reflects an endogenous metabolic adaptation holding therapeutic potential to mitigate energy deficits in neurodegenerative diseases.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

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• osf:zfdga — at OSF; found in “Data Availability Statement”

Data Availability Statement

The data presented in this study are available on: https://osf.io/zfdga/overview?view_only=91980eea9f0142f291ad6550f670fe5c (accessed on 30 April 2026).

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 5 authors, 5 keywords, 10 MeSH terms, 4 funders, 42 references.

Cite

This paper

Riou, A., Broeglin, A., Papassotiropoulos, A., Eckert, A., & Grimm, A. (2026). Compensatory Intercellular Mitochondrial Transfer Improves Bioenergetics in P301L Tau-Affected Neuronal Cells. Cells, 15(12), 1101. https://doi.org/10.3390/cells15121101

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