Mas receptor activation promotes mitophagy and preserves neuronal function after traumatic brain injury.

Abstract

Traumatic brain injury (TBI) is a leading global cause of death and long-term disability, primarily due to secondary injury mechanisms such as mitochondrial dysfunction and impaired mitophagy，the selective degradation of damaged mitochondria. While the ACE2/Angiotensin-(1-7)/Mas receptor (MasR) axis is recognized for its neuroprotective effects in various neurological disorders, its role in regulating mitochondrial quality control after TBI remains unclear. In this study, we investigated the regulatory function of MasR in post-traumatic mitophagy using controlled cortical impact (CCI) mice and scratch-injured neuronal cultures. We employed MasR knockdown (MasR-KD) and pharmacological activation with the selective MasR agonist AVE0991 to assess neurobehavioral outcomes, neuronal survival, and mitophagy flux. Activation of MasR significantly improved motor coordination, cognitive performance, and reduced anxiety-like behaviors following TBI, whereas MasR deficiency exacerbated neurological deficits. Histologically, MasR-KD mice exhibited increased neuronal loss, dendritic degeneration, and oxidative stress. In contrast, AVE0991 treatment preserved neuronal integrity and mitochondrial ultrastructure, effects that were abolished in MasR-KD animals. Mechanistically, MasR activation promoted PINK1/Parkin-mediated mitophagy, enhanced TOMM20-LC3 colocalization, stabilized mitochondrial membrane potential, reduced mitochondrial ROS production, and improved respiratory capacity. In vitro, Ang-(1-7) restored mitophagy flux through MasR-dependent clearance of damaged mitochondria, as confirmed by mt-Keima assays. Collectively, these findings identify MasR as an endogenous regulator of PINK1/Parkin-mediated mitophagy and mitochondrial homeostasis following TBI and demonstrate that MasR signaling is required for preserving mitochondrial function and neurological outcomes after injury.