Medium-chain Fatty Acids as Biomarkers of Mitochondrial Dysfunction in Traumatic Brain Injury EBioMedicine 12 (2016) 8–9 Contents lists available at ScienceDirect EBioMedicine journal homepage: www.ebiomedicine.com Commentary Medium-chain Fatty Acids as Biomarkers of Mitochondrial Dysfunction in Traumatic Brain Injury Raúl González-Domínguez Department of Chemistry, Faculty of Experimental Sciences, University of Huelva, 21007, Spain International Campus of Excellence CeiA3, University of Huelva, 21007, Spain DOI of original article: http://dx.doi.org/10.1016/j.ebio E-mail address: raul.gonzalez@dqcm.uhu.es. http://dx.doi.org/10.1016/j.ebiom.2016.09.024 2352-3964/© 2016 The Author. Published by Elsevier B.V a r t i c l e i n f o Article history: Received 16 September 2016 Accepted 22 September 2016 Available online 28 September 2016 Keywords: dative stress, membrane disruption, failures in energy metabolism and neuronal injury, among other pathological processes. In the current issue of EBioMedicine, Orešič et al. (2016) describe the application of a metabolomic platform based on bi-dimensional gas chromatography coupled to high-resolution mass spectrometry (GC × GC-TOF-MS) to identify biomarkers in serum samples that could associ- Medium chain fatty acids Metabolomics Traumatic brain injury Traumatic brain injury (TBI) is a complex disorder with variable eti- ology and severity that nowadays stands as a major cause of death and disability worldwide, principally among children and young people. De- spite the implementation of intensive care strategies at early stages fol- lowing the injury, long-term morbidity of severe TBI still remains high, and many patients may show significant neurologic sequelae even after recovery, which usually persist for years. For this reason, there is a crit- ical need to get a deeper insight into pathological mechanisms occurring in brain after trauma and discover potential biomarkers that could help in diagnosis, staging disease severity, monitoring disease progression, the identification of complications, as well as the development of better strategies for treatment and rehabilitation after injury. TBI pathology begins with a mechanical brain damage, which is followed by complex and dynamic perturbations in multiple molecular pathways in glia and neurons. Thus, holistic approaches such as metabolomics stand out as suitable tools for characterizing these metabolic alterations. Metabolo- mics can be defined as the comprehensive study of the entire set of me- tabolites from a cell, tissue, organ, body fluid or organism at a specific time, as well as of the metabolic changes observed in response to a ge- netic or environmental perturbation. However, only a few authors have previously reported the application of metabolomic techniques for investigating TBI pathogenesis, usually by employing nuclear mag- netic resonance (1H-NMR) to study the brain and blood metabolome from different animal models (Viant et al., 2005; Bahado-Singh et al., 2016a; Bahado-Singh et al., 2016b). Thereby, it was demonstrated that m.2016.07.015. . This is an open access article under numerous significant disturbances in TBI might be associated with oxi- ate with disease severity and predict the outcomes of TBI patients. For this purpose, two independent cohorts were enrolled with the aim to validate results obtained in the discovery phase, comprising mild, mod- erate and severe TBI patients as well as orthopedic controls. Various metabolomic alterations were detected in serum samples, following the same pattern in all patients but with a proportional degree of change depending on the disease severity, thus suggesting that TBI is character- ized by a specific metabotype. Moreover, some of these metabolites could be also associated with patient clinical outcomes, which were then employed to build a predictive model with good accuracy. Signifi- cant changes were observed in serum levels of different hydroxyl-acids, sugar-derived metabolites as well as amino acids and related com- pounds. Furthermore, many of these metabolites were highly correlated with their content in brain microdialysates, thus evidencing a possible disruption of the blood brain barrier. However, the most relevant find- ing was the increase of two medium chain fatty acids (MCFA), including octanoic and decanoid acids, whose levels remain high in most patients during the first week following the injury, and could be associated with poor outcomes in TBI patients. The accumulation of MCFAs, together with their corresponding acyl-carnitines, is the typical feature of medi- um-chain acyl-coenzyme A dehydrogenase deficiency, the most fre- quent fatty acid oxidation disorder, and one of the most recognizable inborn errors of metabolism (Rinaldo and Matern, 2002). Nevertheless, recent studies have also associated this metabolic signature with other heterogeneous diseases, such as Alzheimer's disease (González- Domínguez et al., 2014), schizophrenia (Liu et al., 2014) and different types of cancer (Hori et al., 2011; Crotti et al., 2016), all of them charac- terized by impaired mitochondrial function. Furthermore, it has been demonstrated that these fatty acids can provoke significant failures in various pathways related to energy metabolism, including the oxidative phosphorylation and the creatine kinase system, and may elicit lipid and protein oxidative damage (Schuck et al., 2009). Thereby, there is considerable evidence that suggests the potential of these circulating MCFAs as biomarkers of mitochondrial dysfunction. the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). http://crossmark.crossref.org/dialog/?doi=10.1016/j.ebiom.2016.09.024&domain=pdf http://dx.doi.org/10.1016/j.ebiom.2016.09.024 http://dx.doi.org/10.1016/j.ebiom.2016.07.015 mailto:raul.gonzalez@dqcm.uhu.es http://dx.doi.org/10.1016/j.ebiom.2016.09.024 http://creativecommons.org/licenses/by-nc-nd/4.0/ http://www.sciencedirect.com/science/journal/03064603 www.ebiomedicine.com 9R. González-Domínguez / EBioMedicine 12 (2016) 8–9 Therefore, it is noteworthy that octanoic and decanoic acids could play a major role in energy crisis associated with mitochondrial failures occurring in traumatic brain injury. However, it remains unclear if these metabolic changes are causative performers of the pathophysiology ob- served or, on the contrary, they are a consequence of these impairments. Thus, a better understanding of pathological mechanisms underlying to these perturbations is necessary to obtain a deeper knowledge about the relationships between TBI and medium-chain fatty acids. To this end, future studies should be undertaken with complementary metabolomic approaches such as reversed phase liquid chromatogra- phy-mass spectrometry in order to elucidate the relevance of lipid me- tabolism and fatty acid β-oxidation in pathogenesis of traumatic brain injury. Disclosure The author declares no conflicts of interest. References Bahado-Singh, R.O., Graham, S.F., Turkoglu, O., Beauchamp, K., Bjorndahl, T.C., Han, B., Mandal, R., Pantane, J., Kowalenko, T., Wishart, D.S., Stahel, P.F., 2016a. Identification of candidate biomarkers of brain damage in a mouse model of closed head injury: a metabolomic pilot study. Metabolomics 12, 42. Bahado-Singh, R.O., Graham, S.F., Han, B., Turkoglu, O., Ziadeh, J., Mandal, R., Er, A., Wishart, D.S., Stahel, P.F., 2016b. Serum metabolomic markers for traumatic brain in- jury: a mouse model. Metabolomics 12, 100. Crotti, S., Agnoletto, E., Cancemi, G., Di Marco, V., Traldi, P., Pucciarelli, S., Nitti, D., Agostini, M., 2016. Altered plasma levels of decanoic acid in colorectal cancer as a new diagnostic biomarker. Anal. Bioanal. Chem. http://dx.doi.org/10.1007/s00216-016- 9743-1. González-Domínguez, R., García-Barrera, T., Gómez-Ariza, J.L., 2014. Using direct infusion mass spectrometry for serum metabolomics in Alzheimer's disease. Anal. Bioanal. Chem. 406, 7137–7148. Hori, S., Nishiumi, S., Kobayashi, K., Shinohara, M., Hatakeyama, Y., Kotani, Y., Hatano, N., Maniwa, Y., Nishio, W., Bamba, T., Fukusaki, E., Azuma, T., Takenawa, T., Nishimura, Y., Yoshida, M., 2011. A metabolomic approach to lung cancer. Lung Cancer 74, 284–292. Liu, M.L., Zheng, P., Liu, Z., Xu, Y., Mu, J., Guo, J., Huang, T., Meng, H.Q., Xie, P., 2014. GC-MS based metabolomics identification of possible novel biomarkers for schizophrenia in peripheral blood mononuclear cells. Mol. BioSyst. 10, 2398–2406. Orešič, M., Posti, J.P., Kamstrup-Nielsen, M.H., Takala, R.S.K., Lingsma, H.F., Mattila, I., Jäntti, S., Katila, A.J., Carpenter, K.L.H., Ala-Seppälä, H., Kyllönen, A., Maanpää, H.R., Tallus, J., Coles, J.P., Heino, I., Frantzén, J., Hutchinson, P.J., Menonemail, D.K., Tenovuoemail, O., Hyötyläinen, T., 2016. Human serum metabolites associate with severity and patient outcomes in traumatic brain injury. EBioMedicine 12, 118–126. Rinaldo, P., Matern, D., 2002. Fatty acid oxidation disorders. Annu. Rev. Physiol. 64, 477–502. Schuck, P.F., Ferreira, G.C., Moura, A.P., Busanello, E.N., Tonin, A.M., Dutra-Filho, C.S., Wajner, M., 2009. Medium-chain fatty acids accumulating in MCAD deficiency elicit lipid and protein oxidative damage and decrease non-enzymatic antioxidant de- fenses in rat brain. Neurochem. Int. 554, 519–525. Viant, M.R., Lyeth, B.G., Miller, M.G., Berman, R.F., 2005. An NMR metabolomic investiga- tion of early metabolic disturbances following traumatic brain injury in a mammalian model. NMR Biomed. 18, 507–516. http://refhub.elsevier.com/S2352-3964(16)30445-5/rf0005 http://refhub.elsevier.com/S2352-3964(16)30445-5/rf0005 http://refhub.elsevier.com/S2352-3964(16)30445-5/rf0005 http://refhub.elsevier.com/S2352-3964(16)30445-5/rf0010 http://refhub.elsevier.com/S2352-3964(16)30445-5/rf0010 http://dx.doi.org/10.1007/s00216-016-9743-1 http://dx.doi.org/10.1007/s00216-016-9743-1 http://refhub.elsevier.com/S2352-3964(16)30445-5/rf0020 http://refhub.elsevier.com/S2352-3964(16)30445-5/rf0020 http://refhub.elsevier.com/S2352-3964(16)30445-5/rf0020 http://refhub.elsevier.com/S2352-3964(16)30445-5/rf0025 http://refhub.elsevier.com/S2352-3964(16)30445-5/rf0030 http://refhub.elsevier.com/S2352-3964(16)30445-5/rf0030 http://refhub.elsevier.com/S2352-3964(16)30445-5/rf0030 http://refhub.elsevier.com/S2352-3964(16)30445-5/rf0035 http://refhub.elsevier.com/S2352-3964(16)30445-5/rf0035 http://refhub.elsevier.com/S2352-3964(16)30445-5/rf0040 http://refhub.elsevier.com/S2352-3964(16)30445-5/rf0040 http://refhub.elsevier.com/S2352-3964(16)30445-5/rf0045 http://refhub.elsevier.com/S2352-3964(16)30445-5/rf0045 http://refhub.elsevier.com/S2352-3964(16)30445-5/rf0045 http://refhub.elsevier.com/S2352-3964(16)30445-5/rf0050 http://refhub.elsevier.com/S2352-3964(16)30445-5/rf0050 http://refhub.elsevier.com/S2352-3964(16)30445-5/rf0050 Medium-�chain Fatty Acids as Biomarkers of Mitochondrial Dysfunction in Traumatic Brain Injury Disclosure References