Mitochondrial Transplantation Increases Bioenergetics and Neurite Outgrowth in Healthy and P301Ltau-Expressing SH-SY5Y 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 leads to bioenergetic deficits and contributes to neuronal cell 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 examines the impact of MT on healthy cells and 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, for 24 and 48 h. Our results demonstrate that MT enhances cell viability, ATP production, mitochondrial membrane potential, and respiration in both healthy and tau-mutant SH-SY5Y cells. In addition, MT reduced mitochondrial superoxide anion levels and promoted neurite outgrowth in both cell lines. Key bioenergetic outcomes were recapitulated in neurons derived from induced pluripotent stem cells (iPSCs) carrying the P301L tau mutation. These findings suggest that MT might be a promising therapeutic strategy to counteract mitochondrial deficits in tauopathies. Importantly, this approach positions mitochondria not as a target but as the therapeutic agent itself. Further studies are warranted to advance MT toward in vivo applications in tau-related neurodegenerative disorders.