N-Formylmethionine Is a Biologically Active Diagnostic Marker of Mild Traumatic Brain Injury

Abstract

Traumatic brain injury (TBI) is a major health problem worldwide. Approximately 2.8 million people in the United States sustain a TBI each year, the majority of which can be classified as mild TBI (mTBI) or concussive injuries. Although mTBI may not cause overt brain damage, it triggers many cellular and molecular changes in brain cells, resulting in neurological, cognitive, and behavioral impairments. Metabolites are released in response to mTBI and can serve as diagnostic markers, as well as potentially contributing to ongoing pathophysiological changes. N-formylmethionine (fMet) is used as the first amino acid for protein synthesis in mitochondria, bacteria, and chloroplasts. Both formylated peptides and free fMet have been detected in human plasma. While a number of studies have demonstrated that formylated peptides can activate the innate immune response, less is known about the role of free fMet in health and disease. In this study, we quantified the free fMet concentration in plasma samples obtained from persons who have sustained an mTBI and compared it with the plasma concentrations detected in healthy volunteers. Our results show that the plasma levels of fMet increased within 24 h of a documented mTBI in both males and females. Receiver operator characteristic (ROC) analysis indicated that the acute change in plasma fMet (<48 h after an injury) has an area under ROC (AUROC) of 0.82 in identifying an mTBI. Interestingly, when fMet was measured in plasma samples collected from these patients 3 months later, it remained elevated and had an AUROC of 0.88. The systemic administration of fMet to mTBI mice impaired brain mitochondrial function, suggesting that it may affect ongoing mTBI pathophysiology.