Efavirenz alters mitochondrial respiratory function in cultured neuron and glial cell lines

J Antimicrob Chemother. 2015 Aug;70(8):2249-54. doi: 10.1093/jac/dkv098. Epub 2015 Apr 29.

Abstract

Background: The NNRTI efavirenz is among the most widely employed antiretroviral drugs. Although it is considered safe, efavirenz has been linked with several adverse effects including neurological manifestations, which appear in the majority of the patients on efavirenz-containing regimens. The molecular mechanisms responsible for these manifestations are not understood, but mounting evidence points to altered brain bioenergetics.

Methods: We evaluated the effect of short-term efavirenz treatment on the mitochondrial respiratory function of cultured glioblastoma and differentiated neuroblastoma cell lines using a Seahorse Extracellular Flux Analyzer.

Results: Incubation with efavirenz provoked a significant and concentration-dependent decrease in basal respiration and specifically in ATP production-coupled O2 consumption in both SH-SY5Y and U-251MG cells, with the effect being more pronounced in the latter. In contrast, efavirenz did not alter mitochondrial proton leakage in either of the cell types. Efavirenz led to a decrease in the respiratory control ratio as well as to a reduction in the maximal respiration rate and spare respiratory capacity in both U-251MG and SH-SY5Y cells, the former cells being more susceptible.

Conclusions: These findings reveal that efavirenz specifically alters mitochondrial respiration, which is of relevance for a better understanding of the molecular mechanisms responsible for the efavirenz-associated neurological effects that have been recorded in clinical situations.

Keywords: HIV; mitochondria; neurotoxicity; respiration; side effects.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Anti-Retroviral Agents / pharmacology*
  • Benzoxazines / pharmacology*
  • Cell Line
  • Cell Respiration / drug effects*
  • Energy Metabolism / drug effects
  • Humans
  • Mitochondria / drug effects*
  • Mitochondria / metabolism
  • Neuroglia / drug effects*
  • Neuroglia / physiology
  • Neurons / drug effects*
  • Neurons / physiology

Substances

  • Anti-Retroviral Agents
  • Benzoxazines
  • Adenosine Triphosphate
  • efavirenz