Oxygen Glucose Deprivation in Rat Hippocampal Slice Cultures Results in Alterations in Carnitine Homeostasis and Mitochondrial Dysfunction

Hdl Handle:
http://hdl.handle.net/10675.2/728
Title:
Oxygen Glucose Deprivation in Rat Hippocampal Slice Cultures Results in Alterations in Carnitine Homeostasis and Mitochondrial Dysfunction
Authors:
Rau, Thomas F.; Lu, Qing; Sharma, Shruti; Sun, Xutong; Leary, Gregory; Beckman, Matthew L.; Hou, Yali; Wainwright, Mark S.; Kavanaugh, Michael ( 0000-0002-3455-703X ) ; Poulsen, David J.; Black, Stephen M.
Abstract:
Mitochondrial dysfunction characterized by depolarization of mitochondrial membranes and the initiation of mitochondrial-mediated apoptosis are pathological responses to hypoxia-ischemia (HI) in the neonatal brain. Carnitine metabolism directly supports mitochondrial metabolism by shuttling long chain fatty acids across the inner mitochondrial membrane for beta-oxidation. Our previous studies have shown that HI disrupts carnitine homeostasis in neonatal rats and that L-carnitine can be neuroprotective. Thus, this study was undertaken to elucidate the molecular mechanisms by which HI alters carnitine metabolism and to begin to elucidate the mechanism underlying the neuroprotective effect of L-carnitine (LCAR) supplementation. Utilizing neonatal rat hippocampal slice cultures we found that oxygen glucose deprivation (OGD) decreased the levels of free carnitines (FC) and increased the acylcarnitine (AC): FC ratio. These changes in carnitine homeostasis correlated with decreases in the protein levels of carnitine palmitoyl transferase (CPT) 1 and 2. LCAR supplementation prevented the decrease in CPT1 and CPT2, enhanced both FC and the ACâ ¶FC ratio and increased slice culture metabolic viability, the mitochondrial membrane potential prior to OGD and prevented the subsequent loss of neurons during later stages of reperfusion through a reduction in apoptotic cell death. Finally, we found that LCAR supplementation preserved the structural integrity and synaptic transmission within the hippocampus after OGD. Thus, we conclude that LCAR supplementation preserves the key enzymes responsible for maintaining carnitine homeostasis and preserves both cell viability and synaptic transmission after OGD.
Citation:
PLoS One. 2012 Sep 11; 7(9):e40881
Issue Date:
11-Sep-2012
URI:
http://hdl.handle.net/10675.2/728
DOI:
10.1371/journal.pone.0040881
PubMed ID:
22984394
PubMed Central ID:
PMC3439445
Type:
Article
ISSN:
1932-6203
Appears in Collections:
Vascular Biology Center: Faculty Research and Publication

Full metadata record

DC FieldValue Language
dc.contributor.authorRau, Thomas F.en_US
dc.contributor.authorLu, Qingen_US
dc.contributor.authorSharma, Shrutien_US
dc.contributor.authorSun, Xutongen_US
dc.contributor.authorLeary, Gregoryen_US
dc.contributor.authorBeckman, Matthew L.en_US
dc.contributor.authorHou, Yalien_US
dc.contributor.authorWainwright, Mark S.en_US
dc.contributor.authorKavanaugh, Michaelen_US
dc.contributor.authorPoulsen, David J.en_US
dc.contributor.authorBlack, Stephen M.en_US
dc.date.accessioned2012-10-26T16:40:55Z-
dc.date.available2012-10-26T16:40:55Z-
dc.date.issued2012-09-11en_US
dc.identifier.citationPLoS One. 2012 Sep 11; 7(9):e40881en_US
dc.identifier.issn1932-6203en_US
dc.identifier.pmid22984394en_US
dc.identifier.doi10.1371/journal.pone.0040881en_US
dc.identifier.urihttp://hdl.handle.net/10675.2/728-
dc.description.abstractMitochondrial dysfunction characterized by depolarization of mitochondrial membranes and the initiation of mitochondrial-mediated apoptosis are pathological responses to hypoxia-ischemia (HI) in the neonatal brain. Carnitine metabolism directly supports mitochondrial metabolism by shuttling long chain fatty acids across the inner mitochondrial membrane for beta-oxidation. Our previous studies have shown that HI disrupts carnitine homeostasis in neonatal rats and that L-carnitine can be neuroprotective. Thus, this study was undertaken to elucidate the molecular mechanisms by which HI alters carnitine metabolism and to begin to elucidate the mechanism underlying the neuroprotective effect of L-carnitine (LCAR) supplementation. Utilizing neonatal rat hippocampal slice cultures we found that oxygen glucose deprivation (OGD) decreased the levels of free carnitines (FC) and increased the acylcarnitine (AC): FC ratio. These changes in carnitine homeostasis correlated with decreases in the protein levels of carnitine palmitoyl transferase (CPT) 1 and 2. LCAR supplementation prevented the decrease in CPT1 and CPT2, enhanced both FC and the ACâ ¶FC ratio and increased slice culture metabolic viability, the mitochondrial membrane potential prior to OGD and prevented the subsequent loss of neurons during later stages of reperfusion through a reduction in apoptotic cell death. Finally, we found that LCAR supplementation preserved the structural integrity and synaptic transmission within the hippocampus after OGD. Thus, we conclude that LCAR supplementation preserves the key enzymes responsible for maintaining carnitine homeostasis and preserves both cell viability and synaptic transmission after OGD.en_US
dc.subjectResearch Articleen_US
dc.subjectBiologyen_US
dc.subjectBiochemistryen_US
dc.subjectBioenergeticsen_US
dc.subjectEnergy-Producing Organellesen_US
dc.subjectMetabolismen_US
dc.subjectBiosynthesisen_US
dc.subjectModel Organismsen_US
dc.subjectAnimal Modelsen_US
dc.subjectRaten_US
dc.subjectMolecular Cell Biologyen_US
dc.subjectCell Deathen_US
dc.subjectCellular Stress Responsesen_US
dc.subjectNeuroscienceen_US
dc.subjectMedicineen_US
dc.subjectNeurologyen_US
dc.titleOxygen Glucose Deprivation in Rat Hippocampal Slice Cultures Results in Alterations in Carnitine Homeostasis and Mitochondrial Dysfunctionen_US
dc.typeArticleen_US
dc.identifier.pmcidPMC3439445en_US
dc.contributor.corporatenameVascular Biology Center-

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