3-Nitropropionic Acid

3-Nitropropionic acid (3-NP) is an irreversible inhibitor of mitochondrial respiratory Complex II succinate dehydrogenase, resulting in energy depletion through disruption of the electron transport chain.^1,2,3 This compound is a natural toxin of certain plants and fungi. Administration of 3-NP to rats (12 mg/kg per day) produces progressive striatal degeneration, while lower doses (8 mg/kg daily) in nonhuman primates results in neuropathologic and clinical features of Huntington’s disease.¹ Conversely, Huntington’s disease results in a loss of Complex II activity.² 3-NP also induces convulsions and is used to examine interventions effective in a mouse model of epilepsy.⁴

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1. Brouillet, E., Hantraye, P., Ferrante, R.J., et al. Chronic mitochondrial energy impairment produces selective striatal degeneration and abnormal choreiform movements in primates. Proc. Natl. Acad. Sci. USA 92, 7105-7109 (1995).

2. Huang, L., Sun, G., Cobessi, D., et al. 3-Nitropropionic acid is a suicide inhibitor of mitochondrial respiration that, upon oxidation by complex II, forms a covalent adduct with a catalytic base arginine in the active site of the enzyme. The Journal of Biological Chemisty 281(9), 5965-5972 (2006).

3. Ayala-Peña, S. Role of oxidative DNA damage in mitochondrial dysfunction and Huntington’s disease pathogenesis. Free Radic. Biol. Med. 62, 102-110 (2013).

4. Zuchora, B., Tursji, W.A., Wielosz, M., et al. Protective effect of adenosine receptor agonists in a new model of epilepsy--seizures evoked by mitochondrial toxin, 3-nitropropionic acid, in mice. Neurosci. Lett. 305(2), 91-94 (2001).