title: Reduction of brain mitochondrial β-oxidation impairs complex I and V in chronic alcohol intake: the underlying mechanism for neurodegeneration.
abstract: Neuropathy and neurocognitive deficits are common among chronic alcohol users, which are believed to be associated with mitochondrial dysfunction in the brain. The specific type of brain mitochondrial respiratory chain complexes (mRCC) that are adversely affected by alcohol abuse has not been studied. Thus, we examined the alterations of mRCC in freshly isolated mitochondria from mice brain that were pair-fed the ethanol (4% v/v) and control liquid diets for 7-8 weeks. We observed that alcohol intake severely reduced the levels of complex I and V. A reduction in complex I was associated with a decrease in carnitine palmitoyltransferase 1 (cPT1) and cPT2 levels. The mitochondrial outer (cPT1) and inner (cPT2) membrane transporter enzymes are specialized in acylation of fatty acid from outer to inner membrane of mitochondria for ATP production. Thus, our results showed that alterations of cPT1 and cPT2 paralleled a decrease β-oxidation of palmitate and ATP production, suggesting that impairment of substrate entry step (complex I function) can cause a negative impact on ATP production (complex V function). Disruption of cPT1/cPT2 was accompanied by an increase in cytochrome C leakage, while reduction of complex I and V paralleled a decrease in depolarization of mitochondrial membrane potential (ΔΨ, monitored by JC-1 fluorescence) and ATP production in alcohol intake. We noted that acetyl-L-carnitine (ALC, a cofactor of cPT1 and cPT2) prevented the adverse effects of alcohol while coenzyme Q10 (CoQ10) was not very effective against alcohol insults. These results suggest that understanding the molecular, biochemical, and signaling mechanisms of the CNS mitochondrial β-oxidation such as ALC can mitigate alcohol related neurological disorders.
authors: Neurovascular Oxidative Injury Laboratory, Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska, USA. jhaorah@unmc.edu
authors: James
authors: J
authors: Haorah
authors: Travis J
authors: TJ
authors: Rump
authors: Huangui
authors: H
authors: Xiong
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000437:Alcoholism / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism*; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000378:metabolism; D002334:Carnitine O-Palmitoyltransferase / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D045222:Electron Transport Chain Complex Proteins / Q000378:metabolism*; D000431:Ethanol / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000378:metabolism; D010084:Oxidation-Reduction; D009435:Synaptic Transmission / Q000187:drug effects; D013997:Time Factors; D014451:Ubiquinone / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D045222:Electron Transport Chain Complex Proteins; D014451:Ubiquinone; D000431:Ethanol; D000255:Adenosine Triphosphate; D045304:Cytochromes c; D002334:Carnitine O-Palmitoyltransferase; C024989:coenzyme Q10
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