Mitochondrial transplantation improves bioenergetics and neurite outgrowth in disease-associated P301Ltau-expressing neuronal cells

Tauopathies are neurodegenerative diseases characterized by the abnormal accumulation of tau protein in neurons, leading to cognitive impairment. A common feature of these disorders is mitochondrial dysfunction, which results in bioenergetic deficits and contributes to neuronal death. As neurons have high energy demands, impaired mitochondrial function directly affects their viability and function. Thus, mitochondria represent an attractive target for neuroprotective strategies in tauopathies. Mitochondrial transplantation (MT) is an emerging therapeutic approach to restoring cellular bioenergetics. Although MT has shown promise in various models of brain diseases, its efficacy has not been evaluated in the context of tau-induced mitochondrial dysfunction. This study investigates the therapeutic potential of MT in a cellular model of tauopathy. Mitochondria were freshly isolated from astrocytic cells and transplanted into healthy SH-SY5Y neuroblastoma cells and SH-SY5Y cells overexpressing the P301L tau mutation. Bioenergetic and neuroplastic parameters were assessed 24 and 48h post-transplantation. Our results demonstrate that MT enhances cell viability, ATP production, mitochondrial membrane potential, and respiration in both healthy and tau-mutant neuronal cells. In addition, MT reduced mitochondrial superoxide anion levels and promoted neurite outgrowth in both cell lines. These findings suggest that MT is a promising therapeutic strategy for tauopathies. Importantly, this approach positions mitochondria not as a target but as the therapeutic agent itself. Further studies are warranted to advance mitochondrial transplantation toward clinical applications in tau-related neurodegenerative disorders.