Inhibition of adenine nucleotide translocator pore function and protection against apoptosis in vivo by an HIV protease inhibitor
Joel G.R. Weaver, … , Guido Kroemer, Andrew D. Badley
Joel G.R. Weaver, … , Guido Kroemer, Andrew D. Badley
Published July 1, 2005
Citation Information: J Clin Invest. 2005;115(7):1828-1838. https://doi.org/10.1172/JCI22954.
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Research Article Infectious disease

Inhibition of adenine nucleotide translocator pore function and protection against apoptosis in vivo by an HIV protease inhibitor

Abstract

Inhibitors of HIV protease have been shown to have antiapoptotic effects in vitro, yet whether these effects are seen in vivo remains controversial. In this study, we have evaluated the impact of the HIV protease inhibitor (PI) nelfinavir, boosted with ritonavir, in models of nonviral disease associated with excessive apoptosis. In mice with Fas-induced fatal hepatitis, Staphylococcal enterotoxin B–induced shock, and middle cerebral artery occlusion–induced stroke, we demonstrate that PIs significantly reduce apoptosis and improve histology, function, and/or behavioral recovery in each of these models. Further, we demonstrate that both in vitro and in vivo, PIs block apoptosis through the preservation of mitochondrial integrity and that in vitro PIs act to prevent pore function of the adenine nucleotide translocator (ANT) subunit of the mitochondrial permeability transition pore complex.

Authors

Joel G.R. Weaver, Agathe Tarze, Tia C. Moffat, Morgane LeBras, Aurelien Deniaud, Catherine Brenner, Gary D. Bren, Mario Y. Morin, Barbara N. Phenix, Li Dong, Susan X. Jiang, Valerie L. Sim, Bogdan Zurakowski, Jessica Lallier, Heather Hardin, Peter Wettstein, Rolf P.G. van Heeswijk, Andre Douen, Romano T. Kroemer, Sheng T. Hou, Steffany A.L. Bennett, David H. Lynch, Guido Kroemer, Andrew D. Badley

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Figure 4

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NFV blocks Bax-induced apoptosis but not Bax activation. (A) Mouse liver...
NFV blocks Bax-induced apoptosis but not Bax activation. (A) Mouse liver mitochondria were incubated with 10 μM of NFV followed by 1 μM Vpr-derived peptide, 0.5 mM ATR, or 4 μM Bax while absorption was assessed at 545 nm. The loss of absorption induced by 0.5 mM ATR within 20 minutes was considered at 100% of large amplitude swelling. All experiments were reproduced 3 times. (B) Jurkat T cells were treated with an agonistic anti-Fas antibody in the presence or absence of NFV and stained with Hoechst 33342 for nuclear morphology, an antibody (or isotype control) specific for activated Bax, and an Alexa Fluor–conjugated secondary antibody. All cells were stained with Hoechst and varying combinations of NFV or DMSO, CH-11, and anti-Bax or isotype antibody as indicated. (C) Jurkat T cells were transfected with Bax, and immediately following transfection, NFV or control was added and ΔΨm was assessed.