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Mitochondria are essential for neuronal function because they serve not only to sustain energy and redox homeostasis but also are harbingers of death. A dysregulated mitochondrial network can cascade until function is irreparably lost, dooming cells. TBI is most prevalent in the young and comes at significant personal and societal costs. Traumatic brain injury (TBI) triggers a biphasic and mechanistically heterogenous response and this mechanistic heterogeneity has made the development of standardized treatments challenging. The secondary phase of TBI injury evolves over hours and days after the initial insult, providing a window of opportunity for intervention. However, no FDA approved treatment for neuroprotection after TBI currently exists. With recent advances in detection techniques, there has been increasing recognition of the significance and roles of mitochondrial redox lipid signaling in both acute and chronic central nervous system (CNS) pathologies. Oxidized lipids and their downstream products result from and contribute to TBI pathogenesis. Therapies targeting the mitochondrial lipid composition and redox state show promise in experimental TBI and warrant further exploration. In this review, we provide 1) an overview for mitochondrial redox homeostasis with emphasis on glutathione metabolism, 2) the key mechanisms of TBI mitochondrial injury, 3) the pathways of mitochondria specific phospholipid cardiolipin oxidation, and 4) review the mechanisms of mitochondria quality control in TBI with consideration of the roles lipids play in this process., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Cardiolipin (CL) is a mitochondria-specific phospholipid that is central to maintenance and regulation of mitochondrial bioenergetic and metabolic functions. CL molecular species display great tissue variation with brain exhibiting a distinct, highly diverse CL population. We recently showed that the appearance of unique brain-type CLs in plasma could serve as a brain-specific marker of mitochondrial/tissue injury in patients after cardiac arrest. Mitochondrial dysfunction has been increasingly implicated as a critical mechanism underlying the pathogenesis of traumatic brain injury (TBI). Therefore, we hypothesized that unique, brain-specific CL species from the injured brain are released to the peripheral circulation after TBI. To test this hypothesis, we performed a high-resolution mass spectrometry based phospholipidomics analysis of post-natal day (PND)17 rat brain and plasma after controlled cortical impact. We found a time-dependent increase in plasma CLs after TBI including the aforementioned brain-specific CL species early after injury, whereas CLs were significantly decreased in the injured brain. Compositional and quantitative correlational analysis suggested a possible release of CL into the systemic circulation following TBI. The identification of brain-type CLs in systemic circulation may indicate underlying mitochondrial dysfunction/loss after TBI. They may have potential as pharmacodynamics response biomarkers for targeted therapies., (Copyright © 2019 Elsevier Inc. All rights reserved.)