Abstract
Mitochondrial dysfunction, the inability to efficiently utilise metabolic fuels and oxygen, contributes to pathological changes following traumatic spinal cord or traumatic brain injury (TBI). In the present study, we tested the hypothesis that succinate supplementation can improve cellular energy state under metabolically stressed conditions in a robust, reductionist in vitro model of mitochondrial dysfunction in which primary mixed glial cultures (astrocytes, microglia and oligodendrocytes) were exposed to the mitochondrial complex I inhibitor rotenone. Cellular response was determined by measuring intracellular ATP, extracellular metabolites (glucose, lactate, pyruvate), and oxygen consumption rate (OCR). Rotenone produced no significant changes in glial ATP levels. However, it induced metabolic deficits as evidenced by lactate/pyruvate ratio (LPR) elevation (a clinically-established biomarker for poor outcome in TBI) and decrease in OCR. Succinate addition partially ameliorated these metabolic deficits. We conclude that succinate can improve glial oxidative metabolism, consistent our previous findings in TBI patients’ brains. The mixed glial cellular model may be useful in developing therapeutic strategies for conditions involving mitochondrial dysfunction, such as TBI.
Highlights
Following traumatic injury to the spinal cord or brain, a complex combination of pathological processes develop, in which cerebral energy perturbations and cellular metabolism play a key role[1,2,3,4,5]
Glia are especially relevant as clinical monitoring of traumatic brain injury (TBI) brain is performed via microdialysis catheters that are predominantly situated in white matter
The cultured cells were exposed to rotenone, which is an inhibitor of complex I of the mitochondrial electron transport chain (ETC), for periods of up to 24 h to induce conditions of metabolic stress, in the presence or absence of disodium succinate
Summary
Following traumatic injury to the spinal cord or brain, a complex combination of pathological processes develop, in which cerebral energy perturbations and cellular metabolism play a key role[1,2,3,4,5]. Succinate is a tricarboxylic acid (TCA) cycle intermediate that interacts directly with the mitochondrial electron transport chain (ETC), enabling a ‘shortcut’ route to ATP production via oxidative metabolism. This has been suggested as a potential therapeutic strategy for TBI11. The aim of the present study was to investigate whether succinate supplementation can rescue the energy state in rat mixed glial cells under experimental metabolic stress conditions using a defined inhibitor of mitochondrial function.
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