Tau–Mitochondria Interactions in Neurodegeneration: Mechanisms and Therapeutic Potential

Tau is a microtubule-associated protein encoded by the MAPT gene and is mainly expressed in neurons. Alternative splicing generates preferentially six isoforms differing in N-terminal inserts (0, 1, or 2N) and microtubule-binding repeats (3R or 4R). Isoform expression varies by cell type, developmental stage, and neuronal maturation. Structurally, 4R isoforms bind and stabilize microtubules more effectively than 3R isoforms, while 3R variants are more prone to oligomerization. Differences among isoforms also affect aggregation and post-translational modification patterns, yet their specific roles in tauopathies remain unclear. Beyond its role in microtubule stabilization, tau is increasingly recognized for its functions in other cellular compartments, particularly mitochondria, where it may contribute to mitochondrial dysfunction in neurodegenerative diseases. Its intrinsically disordered conformation and extensive post-translational modifications enable interactions with multiple mitochondrial components, linking tau biology to broader aspects of neuronal health and pathology. The main focus of this review is to analyze how tau protein interacts with mitochondria and disrupts their function. Literature evidence indicates that tau localizes to the outer mitochondrial membrane, intermembrane space, and matrix, where it interferes with key processes. These include disruption of electron transport chain activity, inhibition of ATP synthase, and reduced ATP production, ultimately compromising neuronal energy supply. In parallel, tau destabilizes microtubule-based trafficking, impairing axonal transport and mitochondrial distribution, while also disrupting fission and fusion dynamics that shape mitochondrial morphology. Quality control pathways are affected as well, with tau altering mitophagy and mitochondria-nucleus signaling. Moreover, tau dysregulates calcium buffering and increases reactive oxygen species production, thereby promoting synaptic dysfunction, oxidative stress, and mitochondrial damage. Collectively, these facts establish tau as a central mediator of mitochondrial impairment and neuronal vulnerability. Elucidating the mechanisms by which tau affects mitochondrial physiology underscores its importance as a therapeutic target, with strategies aimed at preserving mitochondrial integrity offering promising avenues to slow neurodegenerative progression. In the last section, we include examples of clinical applications currently in various phases of testing, some of which show promising potential for implementation.