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Succinate supplementation improves metabolic performance of mixed glial cell cultures with mitochondrial dysfunction

Published version
Peer-reviewed

Type

Article

Change log

Authors

Amaral, AI 
Hutchinson, PJA 
Kotter, MR 
Carpenter, KLH 

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.

Description

Keywords

Animals, Brain Injuries, Traumatic, Cell Proliferation, Cell Survival, Cells, Cultured, Dietary Supplements, Energy Metabolism, Mitochondria, Models, Biological, Neuroglia, Oxygen Consumption, Rats, Rats, Sprague-Dawley, Rotenone, Spinal Cord Injuries, Succinic Acid

Journal Title

Scientific Reports

Conference Name

Journal ISSN

2045-2322
2045-2322

Volume Title

7

Publisher

Nature Publishing Group
Sponsorship
Medical Research Council (G1002277)
TCC (None)