Trigeminal Nerve Stimulation Attenuates Traumatic Brain Injury-Induced Neuronal Damage via CGRP-PINK1 Mitophagy Axis
Secondary damage after traumatic brain injury (TBI) is driven by progressive mitochondrial failure, yet clinically viable strategies to directly safeguard mitochondrial networks remain a major therapeutic gap. Here, we show that non-invasive trigeminal nerve stimulation (TNS), which engages the brain's endogenous oxygen-conserving diving reflex, preserves neuronal survival by directly regulating the mitochondrial PINK1/Parkin quality-control pathway. We demonstrate that TBI induces the pathological aggregation of the outer mitochondrial membrane receptor TOM20, in a CGRP-dependent manner, which affects binding of the damage-sensor PINK1 and renders downstream Parkin-mediated rescue ineffective. TNS-induced neuronal CGRP release prevents this TOM20 aggregation, restoring proper PINK1 function and downstream Parkin activation. This preservation of mitochondrial architecture reinforces the outer membrane's barrier function, limiting pro-apoptotic cytochrome c leakage and supporting NRF2 antioxidant defenses, ultimately reducing progressive infarct expansion and recovering sensorimotor functions. The significance of this work lies in bridging physical neuromodulation directly to the preservation of organelle-level architecture. By demonstrating that stimulation of trigeminal afferents to recruit an oxygen-conserving reflex can stabilize outer membrane signaling architecture and preserve mitochondrial survival machinery, this study outlines a non-pharmacological strategy to protect mitochondrial function and inhibit acute post-traumatic neurodegeneration.