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

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. HouSteffany A.L. Bennett, David H. Lynch, Guido Kroemer, Andrew D. Badley

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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 β-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.

Original languageEnglish (US)
Pages (from-to)1828-1838
Number of pages11
JournalJournal of Clinical Investigation
Volume115
Issue number7
DOIs
StatePublished - Jul 2005

ASJC Scopus subject areas

  • Medicine(all)

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    Weaver, J. G. R., Tarze, A., Moffat, T. C., Lebras, M., Deniaud, A., Brenner, C., Bren, G. D., Morin, M. Y., Phenix, B. N., Dong, L., Jiang, S. X., Sim, V. L., Zurakowski, B., Lallier, J., Hardin, H., Wettstein, P., Van Heeswijk, R. P. G., Douen, A., Kroemer, R. T., ... Badley, A. D. (2005). Inhibition of adenine nucleotide translocator pore function and protection against apoptosis in vivo by an HIV protease inhibitor. Journal of Clinical Investigation, 115(7), 1828-1838. https://doi.org/10.1172/JCI22954