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Complex II Inhibition by 3-NP Causes Mitochondrial Fragmentation and Neuronal Cell Death Via an NMDA- and ROS-Dependent Pathway

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Complex II Inhibition by 3-NP Causes Mitochondrial Fragmentation and Neuronal Cell Death Via an NMDA- and ROS-Dependent Pathway Cell Death and Differentiation (2009) 16, 899–909 & 2009 Macmillan Publishers Limited All rights reserved 1350-9047/09 $32.00 www.nature.com/cdd Complex II inhibition by 3-NP causes mitochondrial fragmentation and neuronal cell death via an NMDA- and ROS-dependent pathway G Liot1, B Bossy1,2, S Lubitz2, Y Kushnareva1, N Sejbuk1 and E Bossy-Wetzel*,1,2 Mitochondrial respiratory complex II inhibition plays a central role in Huntington’s disease (HD). Remarkably, 3-NP, a complex II inhibitor, recapitulates HD-like symptoms. Furthermore, decreases in mitochondrial fusion or increases in mitochondrial fission have been implicated in neurodegenerative diseases. However, the relationship between mitochondrial energy defects and mitochondrial dynamics has never been explored in detail. In addition, the mechanism of neuronal cell death by complex II inhibition remains unclear. Here, we tested the temporal and spatial relationship between energy decline, impairment of mitochondrial dynamics, and neuronal cell death in response to 3-NP using quantitative fluorescence time-lapse microscopy and cortical neurons. 3-NP caused an immediate drop in ATP. This event corresponded with a mild rise in reactive oxygen species (ROS), but mitochondrial morphology remained unaltered. Unexpectedly, several hours after this initial phase, a second dramatic rise in ROS occurred, associated with profound mitochondrial fission characterized by the conversion of filamentous to punctate mitochondria and neuronal cell death. Glutamate receptor antagonist AP5 abolishes the second peak in ROS, mitochondrial fission, and cell death. Thus, secondary excitotoxicity, mediated by glutamate receptor activation of the NMDA subtype, and consequent oxidative and nitrosative stress cause mitochondrial fission, rather than energy deficits per se. These results improve our understanding of the cellular mechanisms underlying HD pathogenesis. Cell Death and Differentiation (2009) 16, 899–909; doi:10.1038/cdd.2009.22; published online 20 March 2009 Huntington’s disease (HD) is a fatal progressive neuro- defect.8 Moreover, mitochondria isolated from the lympho- degenerative disorder with autosomal dominant inheritance. blasts of HD patients, brain tissue of mtHtt mice, and An abnormal CAG expansion coding for a polyglutamine mtHtt-expressing cells all exhibit decreased mitochondrial stretch in the N-terminal region of the huntingtin gene causes membrane potential (DCm), increased susceptibility to HD. Disease results when the polyglutamine stretch contains calcium-induced mitochondrial depolarization, and reduced 40 or more residues, and repeats of 36–39 residues have mitochondrial calcium uptake capacity.3,9 Finally, mtHtt reduced penetrance. The clinical symptoms of HD include causes ultrastructural changes of mitochondria and localizes progressive motor, cognitive, and emotional deficits due to the to the mitochondrial outer membrane,10 where it can form changes in the cortex and striatum. How mutant huntingtin aggregates.3 Incubation of isolated mitochondria with recom- (mtHtt) triggers neurodegeneration is not clear. Among the binant mtHtt protein leads to mitochondrial swelling and proposed mechanisms are transcriptional dysregulation, release of cytochrome c, suggesting a direct effect of the axonal and dendritic transport defects, protein aggregation, protein on mitochondria.10 and excitotoxic pathways mediated by glutamate receptors. 3-Nitropropionic acid (3-NP), an irreversible inhibitor of the In addition to these pathways, there is strong evidence that mitochondrial respiratory complex II and succinate dehydro- deficits in energy metabolism and mitochondria play a pivotal genase, recapitulates HD-like pathology and symptoms in role in HD pathogenesis.1–6 For example, brain tissue of HD primate and rodent models.11 In addition, overexpression of patients1,2 and transgenic mice expressing the mtHtt gene5 complex II subunits reverts mitochondrial defects and exhibit reduced activity of the mitochondrial respiratory prevents cell death in striatal mtHtt neurons.7 Thus, although complexes II, III, and IV. In addition, striatal neuronal cultures it is clear that complex II dysfunction is an important event in expressing mtHtt exhibit decreased expression of respiratory HD pathogenesis,2 the cause of this dysfunction and how it complex II.7 Furthermore, HD patients lose weight despite triggers downstream neuronal cell death is not clear. normal or increased calorie intake and their cortex and basal In healthy neurons, mitochondria often form long filaments ganglia have increased lactate levels, indicative of a metabolic that migrate, fuse, and divide.12 The dynamic properties of 1Apoptosis and Cell Death Program, Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA and 2Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, 4000 Central Florida Blvd., Orlando, FL 32816, USA *Corresponding author: E Bossy-Wetzel, Biomedical Science Center, University of Central Florida, 4000 Central Florida Blvd., Orlando, FL 32816, USA. Tel: þ 407 823 4756; Fax: þ 407 823 0956; E-mail: [email protected] Keywords: mitochondria; Huntington’s disease; nitric oxide; NMDA receptor; excitotoxicity; reactive oxygen species Abbreviations: AP5, D-2-amino-5-phosphonopentanoate; DIV, days in vitro; DMEM, Dulbecco’s Modified Eagle Medium; HD, Huntington’s disease; mtHtt, mutant À À huntingtin; 3-NP, 3-nitropropionic acid; NAC, N-acetyl-L-cysteine; NMDA, N-methyl-D-aspartate; NO, nitric oxide; O2 , superoxide anions; ONOO , peroxynitrite; ROI, region of interest; RT, room temperature; ROS, reactive oxygen species; DCm, mitochondrial membrane potential; zVAD-fmk, N-benzyloxycarbonyl-Val-Ala-Asp- fluoromethylketone Received 04.9.08; revised 03.2.09; accepted 04.2.09; Edited by N Bazan; published online 20.3.09 Mitochondrial fragmentation G Liot et al 900 mitochondria are believed to ensure equal energy and expressing neurons by 3D time-lapse fluorescence metabolite distribution across long neurites. A filamentous microscopy after 3-NP (10 mM) exposure for several hours. mitochondrial morphology correlates with high bioenergetic Six to twelve hours after 3-NP exposure, mitochondria functionality and cell survival. Significantly, mutations in were converted from elongated and filamentous to punctate mitochondrial fusion factors mitofusin 2 (MFN2) and optic (Figure 1B). We were able to differentiate two types atrophy 1 (OPA1), which result in chronic mitochondrial of morphological change. First, a subpopulation of contracting fission, cause neurodegenerative disorders in humans.12 mitochondria, which reduced their length (condensed), In addition, we recently showed that nitric oxide (NO), but did not increase in number (Figure 1Ba). Second, N-methyl-D-aspartate (NMDA), rotenone, and b-amyloid a subpopulation that underwent fragmentation (fission) into peptide, all of which have been implicated in neurodegenera- several smaller sized structures with an increase in number tion, evoke excessive mitochondrial fission and neuronal (Figure 1Bb). Both mitochondrial condensation and frag- cell death.13,14 Finally, we demonstrated that mitochondrial mentation occurred in a single neuron following 3-NP fission occurs in ischemic stroke in vivo and is required exposure. We used the term ‘punctate mitochondria’ for NO-mediated neuronal demise.13 Thus, the importance to describe both of these 3-NP-mediated changes in of mitochondrial fragmentation in neurodegeneration is mitochondrial morphology. becoming increasingly apparent and its potential role in HD-associated mitochondrial dysfunction is an important area for investigation. 3-NP causes a rapid decrease in ATP levels that As respiratory complex II inhibition is functionally implicated precedes changes in mitochondrial morphology. As in HD pathogenesis in humans and animal models,2,3,7,8,10,15 3-NP is an irreversible inhibitor of succinate dehydrogenase we studied here the mechanisms underlying 3-NP-mediated and blocks respiration, we asked whether it affects neuronal injury using time-lapse fluorescence imaging. We intracellular ATP concentration. To evaluate changes used quantitative time-lapse fluorescence imaging to dissect in ATP concentration and correlate them with changes in the sequence of downstream events in response to complex II mitochondrial morphology, we exposed neurons to inhibition. We show that 3-NP evokes two distinct signals on increasing concentrations of 3-NP (0.1–10 mM) and mitochondria. The first signal is a direct effect of 3-NP on measured ATP levels in cell lysates 1, 3, and 6 h later. mitochondrial bioenergetics, causing a dramatic and rapid Treated neurons showed a rapid dose- and time-dependent ATP drop and a mild reactive oxygen species (ROS) increase, ATP decrease. Specifically, as early as 1 h after 3-NP without alteration in mitochondrial morphology and neuronal treatment, ATP levels decreased by 32% at 1 mM 3-NP and survival. The second signal, following several hours later with by 62% at 10 mM 3-NP (Figure 2A). This drop was even variable onset, is characterized by activation of glutamate more severe at 3 h (40% at 1 mM 3-NP and 75% at 10 mM receptors of the NMDA subtype, which in turn causes 3-NP; Figure 2A) and became more dramatic after 6 h, with a a second ROS rise and mitochondrial fragmentation. maximal drop of 22% at 0.1 mM 3-NP and 79% at 10 mM Importantly, this secondary event triggers neuronal cell death. 3-NP (Figure 2A). The raw data of the ATP measurements
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