MOTS-c Peptide Shows Neuroprotective Promise in Traumatic Brain Injury

Traumatic Brain Injury (TBI) is a severe neurological condition resulting from external force, leading to significant morbidity and mortality. Current therapeutic strategies for TBI are largely supportive and lack specific neuroprotective agents to mitigate secondary injury cascades. This study aimed to elucidate the underlying molecular and metabolic mechanisms by which the mitochondrial-derived peptide MOTS-c exerts its neuroprotective effects in a TBI mouse model.

Treatment with MOTS-c significantly improved neurological severity scores, demonstrating a 43% reduction in neurological deficits compared to the TBI vehicle group by day 7 (p<0.001). Integrated transcriptomic and metabolomic analyses revealed that MOTS-c treatment modulated 1,250 differentially expressed genes and 350 significantly altered metabolites. These changes were predominantly enriched in pathways related to mitochondrial function, oxidative phosphorylation, and inflammatory responses. The most significant finding was that MOTS-c restored mitochondrial ATP production by 20% and increased the expression of key mitochondrial biogenesis genes, such as PGC-1α, by 2.5-fold compared to untreated TBI mice. Furthermore, MOTS-c significantly reduced markers of oxidative stress, including malondialdehyde (MDA), by 30% and decreased pro-inflammatory cytokines like IL-6 and TNF-α by 50% in the injured brain tissue.