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Mitophagy in human astrocytes treated with the antiretroviral drug Efavirenz: Lack of evidence or evidence of the lack.

Abstract：

:Efavirenz (EFV), a first generation non-nucleoside analogue reverse transcriptase inhibitor widely employed in combination antiretroviral therapy regimens over the last 20 years, has been associated with a wide range of neuropsychiatric effects and has also been linked with HIV-associated neurocognitive disorder (HAND). EFV has been reported to alter mitochondrial dysfunction and bioenergetics in different cell types, including astrocytes. Here, we analyzed whether this mitochondrial effect is associated with alterations in autophagy and, more specifically, mitophagy. U251-MG cells were exposed to EFV (10 and 25 μM; 24 h) and the effect was compared with that of CCCP - an uncoupler of the mitochondrial membrane potential and widely-employed in vitro inducer of mitophagy - and those of the known pharmacological stressors rotenone and thapsigargin, selected due to reported similarities with EFV. EFV induces autophagy with functional autophagic flux despite the accumulated p62/SQSTM1. However, it fails to activate canonical mitophagy (according to mitochondrial mass and expression of mitophagy-related proteins). The fact that EFV-exposed cells display decreased levels of TOM20, an outer mitochondrial membrane protein, together with the association of TOM20 with autophagosomes (LC3), points to an alternative form of mitochondrial degradation. Moreover, the perinuclear mitochondrial cluster in EFV-treated cells differs from that displayed with CCCP. Also, in EFV-treated cells, p62 was associated with mitochondria, which may be related to the mito-protective function of this autophagic protein. In conclusion, these findings add to the existing knowledge of the EFV-triggered mitochondrial interference, a mechanism that may be implicated in the adverse CNS events observed in the clinics.

journal_name

Antiviral Res

journal_title

Antiviral research

authors

Martinez-Arroyo O,Gruevska A,Victor VM,González-Polo RA,Yakhine-Diop SMS,Fuentes JM,Esplugues JV,Blas-Garcia A,Apostolova N

doi

10.1016/j.antiviral.2019.04.015

subject

Has Abstract

pub_date

2019-08-01 00:00:00

pages

36-50

eissn

0166-3542

issn

1872-9096

pii

S0166-3542(19)30001-4

journal_volume

168

pub_type

杂志文章

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Mitophagy in human astrocytes treated with the antiretroviral drug Efavirenz: Lack of evidence or evidence of the lack.