Abnormal Tau Protein Influences Intercellular Mitochondrial Transfer Between Astrocytic and Neuronal Cells

Abstract

Tauopathies are a group of neurodegenerative diseases characterized by the pathological accumulation of abnormal tau protein. A consequence of tau pathologies is mitochondrial dysfunctions, which affect essential processes such as mitochondrial transport, bioenergetics, and dynamics. Given the high energy demands of neurons, tau-induced mitochondrial impairment significantly contributes to neuronal vulnerability and degeneration. Recent studies have revealed that cells can transfer mitochondria between them to help energy-deficient cells. This process, known as intercellular mitochondrial transfer, occurs through two different pathways: an indirect transfer via extracellular vesicles and a direct transfer via tunneling nanotubes and gap junctions. Given the known impact of abnormal tau protein on mitochondrial transport and actin filament dynamics, we hypothesized that intercellular mitochondrial transfer could be altered in the context of tauopathies. Therefore, this study aimed to investigate mitochondrial transfer between astrocytic and neuronal cells and assess how abnormal tau protein may influence this process. Our results showed that abnormal tau protein enhances mitochondrial transfer from astrocytic to neuronal cells. Notably, this transfer occurs mainly via contact-dependent mechanisms. In both pathological and healthy conditions, the transferred astrocytic mitochondria either fused with the mitochondrial network of recipient cells or were degraded in the lysosomes or remained isolated in the cytosol. Our data highlight a novel pathway by which abnormal tau protein impacts mitochondrial function, namely the transfer of astrocytic mitochondria to neuronal cells.