Abstract
Armcx1 is highly expressed in the brain and is located in the mitochondrial outer membrane of neurons, where it mediates mitochondrial transport. Mitochondrial transport promotes the removal of damaged mitochondria and the replenishment of healthy mitochondria, which are essential for neuronal survival after traumatic brain injury (TBI). This study investigated the role of Armcx1 and its underlying regulator(s) in secondary brain injury (SBI) after TBI. An in vivo TBI model was established in C57BL/6 mice via controlled cortical impact (CCI). Adeno-associated viruses with Armcx1 overexpression and knockdown were constructed and administered to mice by stereotactic cortical injection. Exogenous miR-223-3P mimic or inhibitor was transfected into cultured cortical neurons, which were then scratched to simulate TBI in vitro. The Armcx1 protein level was found to be decreased in peri-lesion tissue, particularly in neurons. The overexpression of Armcx1 significantly reduced TBI-induced neurological dysfunction, apoptosis, axonal injury, and mitochondrial dysfunction, while knockdown of Armcx1 had the opposite effect. Armcx1 was a direct target of miR-223-3P. The miR-223-3P mimic significantly reduced the Armcx1 protein level, while the miR-223-3P inhibitor had the opposite effect. Finally, the miR-223-3P inhibitor significantly improved mitochondrial membrane potential and increased the total length of the neurites without affecting branching numbers, while the miR-223-3P mimic had the opposite effect. In summary, our results suggest that the decreased expression of Armcx1 protein in neurons after experimental TBI aggravates secondary brain injury, which may be regulated by miR-223-3P. Therefore, this study provides a potential therapeutic approach for treating TBI.
The human mitochondrial transport protein family: Identification and protein regions significant for transport function and substrate specificity
