3‐Nitropropionic acid induces autophagy by forming mitochondrial permeability transition pores rather than activatiing the mitochondrial fission pathway. (18th December 2012)

• Record Type: Journal Article
• Authors: Solesio, Maria E; Saez‐Atienzar, Sara; Jordan, Joaquin; Galindo, Maria F
• Is Part Of: British journal of pharmacology. Volume 168:Number 1(2013:Jan.)
• Page Start: 63
• Page End: 75
• Publication Date: 2012-12-18
• Subjects: Huntington's disease -- mitochondrial dynamics -- MPTP -- Drp1 -- Bax -- Mdivi‐1 -- mitochondrial swelling; Pharmacology -- Periodicals; Chemotherapy -- Periodicals; Drug Therapy -- Periodicals; Pharmacology -- Periodicals; 615.1
• DOI: 10.1111/j.1476-5381.2012.01994.x
• Languages: English
• ISSNs: 0007-1188

Abstract

Abstract : BACKGROUND AND PURPOSE Huntington's disease is a neurodegenerative process associated with mitochondrial alterations. Inhibitors of the electron–transport channel complex II, such as 3‐nitropropionic acid (3NP), are used to study the molecular and cellular pathways involved in this disease. We studied the effect of 3NP on mitochondrial morphology and its involvement in macrophagy. EXPERIMENTAL APPROACH Pharmacological and biochemical methods were used to characterize the effects of 3NP on autophagy and mitochondrial morphology. SH‐SY5Y cells were transfected with GFP‐LC3, GFP‐Drp1 or GFP‐Bax to ascertain their role and intracellular localization after 3NP treatment using confocal microscopy. KEY RESULTS Untreated SH‐SY5Y cells presented a long, tubular and filamentous net of mitochondria. After 3NP (5 mM) treatment, mitochondria became shorter and rounder. 3NP induced formation of mitochondrial permeability transition pores, both in cell cultures and in isolated liver mitochondria, and this process was inhibited by cyclosporin A. Participation of the mitochondrial fission pathway was excluded because 3NP did not induce translocation of the dynamin‐related protein 1 (Drp1) to the mitochondria. The Drp1 inhibitor Mdivi‐1 did not affect the observed changes in mitochondrial morphology. Finally, scavengers of reactive oxygen species failed to prevent mitochondrial alterations, while cyclosporin A, but not Mdivi‐1, prevented the generation of ROS. CONCLUSIONS AND IMPLICATIONS There was a direct correlation between formation of mitochondrial permeability transition pores and autophagy induced by 3NP treatment. Activation of autophagy preceded the apoptotic process and was mediated, at least partly, by formation of reactive oxygen species and mitochondrial permeability transition pores. LINKED ARTICLE This article is commented on by González‐Polo et al., pp. 60–62 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476‐5381.2012.02203.x