Abstract
PURPOSE: Mitophagy is an important process in brain damage, and the precise impact on a traumatic brain injury (TBI) model remains unclear. AMP-activated protein kinase (AMPK) regulates mitochondrial homeostasis and mitophagy, which are closely related to the remission of early brain injury. This study sought to explore the mechanism behind AMPK/optic atrophy 1 (OPA1) pathway in TBI via experimental verifications. METHODS: TBI mouse model induced by weight-drop method was applied in this study. Neurological function tests, Nissl staining, TUNEL staining, and transmission electron microscopy were undertaken to assess the effects of mitophagy on the TBI model. Levels of apoptosis-related factors and mitophagy-related indicators were detected to further reveal the molecular regulatory mechanism of mitophagy in TBI. RESULTS: Activation of mitophagy (MK-8722 or rapamycin treatment) reduced the severity of brain damage and mitigated neurological function deficits following TBI. MK-8722 treatment reduced neuronal apoptosis, improved neuronal mitophagy, effectively inhibited the expression of proteins Bcl-2 and Bax, and increased the expression of proteins Parkin, PINK1 and OPA1. Besides, MK-8722 improved TBI through accelerating the AMPK/OPA1 pathway, resulting in increase of mitophagy. CONCLUSION: This study is the first to pinpoint the AMPK/OPA1 pathway's involvement in TBI and the mechanism of mitophagy, thereby providing a good foundation for future experimental studies.