Mechanistic studies on ketamine-induced mitochondrial toxicity in zebrafish embryos.

Abstract

Ketamine, a phencyclidine derivative, is an antagonist of the Ca2+-permeable N-methyl-d-aspartate (NMDA)-type glutamate receptors. It is a pediatric anesthetic and has been implicated in developmental neurotoxicity. Ketamine has also been shown to deplete ATP in mammalian cells. Our previous studies showed that acetyl l-carnitine (ALCAR) prevented ketamine-induced cardiotoxicity and neurotoxicity in zebrafish embryos. Based on our finding that ALCAR's protective effect was blunted by oligomycin A, an inhibitor of ATP synthase, we further investigated the effects of ketamine and ALCAR on ATP levels, mitochondria and ATP synthase in zebrafish embryos. The results demonstrated that ketamine reduced ATP levels in the embryos but not in the presence of ALCAR. Ketamine reduced total mitochondrial protein levels and mitochondrial potential, which were prevented with ALCAR co-treatment. To determine the cause of ketamine-induced ATP deficiency, we explored the status of ATP synthase. The results showed that a subunit of ATP synthase, atp5α1, was transcriptionally down-regulated by ketamine, but not in the presence of ALCAR, although ketamine caused a significant upregulation in another ATP synthase subunit, atp5β and total ATP synthase protein levels. Most of the ATP generated by heart mitochondria are utilized for its contraction and relaxation. Ketamine-treated embryos showed abnormal heart structure, which was abolished with ALCAR co-treatment. This study offers evidence for a potential mechanism by which ketamine could cause ATP deficiency mediated by mitochondrial dysfunction.

• Authors: Bonnie L Robinson, Melanie Dumas, Syed F Ali, Merle G Paule, Qiang Gu, Jyotshna Kanungo
• Journal: Neurotoxicology and teratology (Neurotoxicol Teratol) 2018 Sep - Oct Vol. 69 Pg. 63-72 ISSN: 1872-9738 [Electronic] United States
• PMID: 29225006 (Publication Type: Journal Article)
• Copyright: Published by Elsevier Inc.

Chemical References

• Proteins
• Ketamine
• Acetylcarnitine
• Adenosine Triphosphate
• Mitochondrial Proton-Translocating ATPases

Topics

• Acetylcarnitine (pharmacology)
• Adenosine Triphosphate (metabolism)
• Animals
• Embryo, Nonmammalian (drug effects)
• Ketamine (adverse effects, antagonists & inhibitors)
• Membrane Potential, Mitochondrial (drug effects)
• Mitochondria (drug effects, metabolism)
• Mitochondrial Proton-Translocating ATPases (metabolism)
• Proteins (metabolism)
• Zebrafish