RT Journal Article
SR Electronic
T1 Efavirenz Induces Neuronal Autophagy and Mitochondrial Alterations
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 250
OP 258
DO 10.1124/jpet.114.217869
VO 351
IS 2
A1 Phillip R. Purnell
A1 Howard S. Fox
YR 2014
UL http://jpet.aspetjournals.org/content/351/2/250.abstract
AB Efavirenz (EFV) is a non-nucleoside reverse-transcriptase inhibitor in wide use for the treatment of human immunodeficiency virus infection. Although EFV is generally well tolerated, neuropsychiatric toxicity has been well documented. The toxic effects of EFV in hepatocytes and keratinocytes have been linked to mitochondrial perturbations and changes in autophagy. Here, we studied the effect of EFV on mitochondria and autophagy in neuronal cell lines and primary neurons. In SH-SY5Y cells, EFV induced a drop in ATP production, which coincided with increased autophagy, mitochondrial fragmentation, and mitochondrial depolarization. EFV-induced mitophagy was also detected by colocalization of mitochondria and autophagosomes and use of an outer mitochondrial membrane tandem fluorescent vector. Pharmacologic inhibition of autophagy with 3-methyladenine increased the cytotoxic effect of EFV, suggesting that autophagy promotes cell survival. EFV also reduces ATP production in primary neurons, induces autophagy, and changes mitochondrial morphology. Overall, EFV is able to acutely induce autophagy and mitochondrial changes in neurons. These changes may be involved in the mechanism leading to central nervous system toxicity observed in clinical EFV use.