L-Carnitine and Mildronate Demonstrate Divergent Protective Effects on Mitochondrial DNA Quality Control and Inflammation Following Traumatic Brain Injury.

Traumatic brain injuries (TBIs) are a serious problem affecting individuals of all ages. Mitochondrial dysfunctions represent a significant form of secondary injury and may serve as a promising target for therapeutic intervention. Our research demonstrated that craniotomy, which precedes the experimental induction of trauma in mice, can cause considerable damage to mitochondrial DNA (mtDNA), disrupt the regulatory expression of angiogenesis, and increase inflammation. However, the reduction in the mtDNA copy number and glial activation occur only after a direct impact to the brain. We explored two potential therapeutic agents: the dietary supplement L-carnitine-a potential reserve source of ATP for the brain-and the cardiac drug mildronate, which inhibits L-carnitine but activates alternative compensatory pathways for the brain to adapt to metabolic disturbances. We found that L-carnitine injections could protect against mtDNA depletion by promoting mitochondrial biogenesis. However, they also appeared to aggravate inflammatory responses, likely due to changes in the composition of the gut microbiome. On the other hand, mildronate enhanced the expression of genes related to angiogenesis while also reducing local and systemic inflammation. Therefore, both compounds, despite their opposing metabolic effects, have the potential to be used in the treatment of secondary injuries caused by TBI.