Naja mossambica mossambica Cobra Cardiotoxin Targets Mitochondria to Disrupt Mitochondrial Membrane Structure and Function
by
Boris Zhang 1, Feng Li 2, Zhengyao Chen 2, Indira H. Shrivastava 3,4, Edward S. Gasanoff 2,*
and Ruben K. Dagda 1,*
Boris Zhang 1, Feng Li 2, Zhengyao Chen 2, Indira H. Shrivastava 3,4, Edward S. Gasanoff 2,* and Ruben K. Dagda 1,*
1
University of Nevada, Reno School of Medicine, Department of Pharmacology, Reno, NV 89557, USA
2
STEM Program, Science Department, Chaoyang KaiWen Academy, North Dongba Road, Beijing 100016, China
3
Department of Computational and System Biology, University of Pittsburgh, PA, 15260, USA
4
Department of Environmental and Occupational Health, University of Pittsburgh, PA,15260, USA
*
Authors to whom correspondence should be addressed.
Toxins 2019, 11(3), 152; https://doi.org/10.3390/toxins11030152
Received: 18 February 2019 / Revised: 1 March 2019 / Accepted: 5 March 2019 / Published: 8 March 2019
(This article belongs to the Special Issue Toxins-Membrane Interactions)
Cobra venom cardiotoxins (CVCs) can translocate to mitochondria to promote apoptosis by eliciting mitochondrial dysfunction. However, the molecular mechanism(s) by which CVCs are selectively targeted to the mitochondrion to disrupt mitochondrial function remains to be elucidated. By studying cardiotoxin from Naja mossambica mossambica cobra (cardiotoxin VII4), a basic three-fingered S-type cardiotoxin, we hypothesized that cardiotoxin VII4 binds to cardiolipin (CL) in mitochondria to alter mitochondrial structure/function and promote neurotoxicity. By performing confocal analysis, we observed that red-fluorescently tagged cardiotoxin rapidly translocates to mitochondria in mouse primary cortical neurons and in human SH-SY5Y neuroblastoma cells to promote aberrant mitochondrial fragmentation, a decline in oxidative phosphorylation, and decreased energy production. In addition, by employing electron paramagnetic resonance (EPR) and protein nuclear magnetic resonance (1H-NMR) spectroscopy and phosphorescence quenching of erythrosine in model membranes, our compiled biophysical data show that cardiotoxin VII4 binds to anionic CL, but not to zwitterionic phosphatidylcholine (PC), to increase the permeability and formation of non-bilayer structures in CL-enriched membranes that biochemically mimic the outer and inner mitochondrial membranes. Finally, molecular dynamics simulations and in silico docking studies identified CL binding sites in cardiotoxin VII4 and revealed a molecular mechanism by which cardiotoxin VII4 interacts with CL and PC to bind and penetrate mitochondrial membranes.
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Keywords:
cobra cardiotoxin; mitochondria; cardiolipin; mitochondrial dysfunction; non-bilayer membrane structures
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MDPI and ACS Style
Zhang, B.; Li, F.; Chen, Z.; Shrivastava, I.H.; Gasanoff, E.S.; Dagda, R.K. Naja mossambica mossambica Cobra Cardiotoxin Targets Mitochondria to Disrupt Mitochondrial Membrane Structure and Function. Toxins 2019, 11, 152.
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