Formoterol improves the deficits of mitochondrial homeostasis including dynamic and transport in human SH-SY5Y neuroblastoma cells induced by mitochondrial UQCRC1 mutation in human neuronal SH-SY5Y cells via a β2-adrenoreceptor activation

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Formoterol, a β2-adrenergic receptor (β2AR) agonist, has been showed to support mitochondrial biogenesis in various diseases. However, its efficacy is controversial in Parkinson’s disease (PD) and its regulatory mechanism of mitochondrial homeostasis remains unclear. This study used a cell model of human reductase core protein (UQCRC1) variants in familial parkinsonism, which expressed mitochondrial dysfunction and dynamic imbalance, to explore the therapeutic effects of formoterol and their underlying mechanism. The results indicated that formoterol treatment for 24 h improved cell proliferation and neural cell activity and afforded neuroprotection against oxidative-stress-induced cell death. Furthermore, mitochondrial function, including mitochondrial DNA copy number, respiratory rate, and complex III activation, was comprehensive recovered, as was the dynamic balance of fusion/fission events. Formoterol treatment properly induced mitochondrial fission and reduced the extensive hypertubulation observed. The underlying mechanism of action of the drug may proceed through the restoration of the ERK signal and the inhibition of Akt overaction in mutant cells, thus significantly upregulating the mitochondrial fission protein Drp-1, including its phosphorylation at Ser616 and dephosphorylation at Ser637, as well as Pink-1, in contrast with the fusion protein Mfn2. Moreover, formoterol contributed to the segregation of healthy mitochondria for distribution and mitochondrial transport, as our data revealed the facilitation of mitochondrial anterograde movement and mobility by the drug, to normalize mitochondrial distribution in mutant cells. This study provided preliminary evidence that formoterol offers neuroprotection and acts as a balance regulator of mitochondrial dynamic to improvement of mitochondrial homeostasis, which renders it a promising therapeutic candidate for PD.

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