Dl-3-n-butylphthalide protects against ischemic stroke by enhancing mitochondrial function via MT-CO1 upregulation

Mitochondrial dysfunction is a key determinant of neuronal death and a promising therapeutic target in ischemic stroke. Dl-3-n-butylphthalide (NBP), an approved neuroprotective agent in China, has been shown to improve mitochondrial integrity, yet its precise molecular mechanisms remain unclear. This study aimed to determine whether NBP exerts neuroprotection by upregulating mitochondrial cytochrome c oxidase subunit 1 (MT-CO1) and to clarify the contribution of MT-CO1 to mitochondrial function recovery.

MT-CO1 expression was measured in the circulation from acute ischemic stroke participants before and following NBP therapy. In SH-SY5Y cells under OGD/R treatment, the action of NBP on mitochondrial bioenergetics, oxidative stress, and apoptosis were assessed. MT-CO1 knockdown was used to determine mechanistic involvement.

NBP significantly increased MT-CO1 expression both in vivo and in vitro, improved mitochondrial membrane voltage and ATP production, reduced ROS generation, and decreased apoptosis. MT-CO1 silencing markedly attenuated these protective effects.

NBP protects against ischemia-induced mitochondrial dysfunction partly through MT-CO1 upregulation, supporting MT-CO1 as a potential therapeutic target for mitochondrial function protection in ischemic stroke.