3-Nitropropionic acid, produced by certain plants and fungi, is a substance that specifically inhibits mitochondrial respiratory chain complex II. 3-Nitropropionic acid exhibits potent antimycobacterial activity with the minimum inhibition concentration of 3.3µM, but is inactive against NCI-H187, BC, KB, and Vero cell lines. 3-Nitropropionic acid, which produces neurodegenerative lesions, is commonly used to establish animal models of Huntington's disease. 3-Nitropropionic acid can also be used to induce epilepsy models[1][2].
In vitro, 3-Nitropropionic acid (5mM; 3h) induced autophagy and disrupted mitochondrial morphology in SH-SY5Y cells[3]. 3-Nitropropionic acid (5mM; 30min) induced swelling in mitochondria isolated from rat liver[3]. 3-Nitropropionic acid (0.1–5mM; 24h) did not affect granulosa cell viability, while 5-10mM significantly inhibited viability in a dose-dependent manner[4]. Treatment with 3-Nitropropionic acid (5mM; 24h) induced ROS production and apoptosis and inhibits the viability of granulosa cells in geese[4]. 3-Nitropropionic acid (0-15mM; 48h) induced a dose-dependent decrease in the number of primary hippocampal neurons[5].
In vivo, a single injection of 3-Nitropropionic acid (100-120mg/kg; i.p.) induced epileptic seizures in mice within 120min, manifesting as tremors or head twitching[6]. 3-Nitropropionic acid (20mg/kg/d; i.p.; 4d) increased lipid peroxidation in the striatum and synaptosomes, while decreasing enzyme activity and increasing SOD activity in both the striatum and cortex in Wistar rats[7].
References:
[1] Huang LS, 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. J Biol Chem. 2006;281(9):5965-5972.
[2] Chomcheon P, Wiyakrutta S, Sriubolmas N, Ngamrojanavanich N, Isarangkul D, Kittakoop P. 3-Nitropropionic acid (3-NPA), a potent antimycobacterial agent from endophytic fungi: is 3-NPA in some plants produced by endophytes?. J Nat Prod. 2005;68(7):1103-1105.
[3] Solesio ME, Saez-Atienzar S, Jordan J, Galindo MF. 3-Nitropropionic acid induces autophagy by forming mitochondrial permeability transition pores rather than activating the mitochondrial fission pathway. Br J Pharmacol. 2013;168(1):63-75.
[4] Kang B, Wang X, Xu Q, Wu Y, Si X, Jiang D. Effect of 3-nitropropionic acid inducing oxidative stress and apoptosis of granulosa cells in geese. Biosci Rep. 2018;38(5):BSR20180274.
[5] Pang Z, Geddes JW. Mechanisms of cell death induced by the mitochondrial toxin 3-nitropropionic acid: acute excitotoxic necrosis and delayed apoptosis. J Neurosci. 1997;17(9):3064-3073.
[6] Urbanska EM, Blaszczak P, Saran T, Kleinrok Z, Turski WA. Mitochondrial toxin 3-nitropropionic acid evokes seizures in mice. Eur J Pharmacol. 1998;359(1):55-58.
[7] Túnez I, Montilla P, Del Carmen Muñoz M, Feijóo M, Salcedo M. Protective effect of melatonin on 3-nitropropionic acid-induced oxidative stress in synaptosomes in an animal model of Huntington's disease. J Pineal Res. 2004;37(4):252-256.