Mechanism of 3‐nitropropionic acid‐induced membrane permeability transition of isolated mitochondria and its suppression by L‐carnitine

Abstract

3-Nitropropionic acid (3NP) functions as an irreversible inhibitor of succinic acid dehydrogenase (complex II) and induces neuronal disorders in rats similar to those in patients with Huntington's disease. It is well known that L-carnitine (LC), a carrier of long chain fatty acid into the mitochondrial matrix, attenuates the neuronal degeneration in 3NP-treated rats. From these findings it has been suggested that 3NP induces certain neuronal cell death through mitochondrial dysfunction and that LC preserves the neurons against the dysfunction of mitochondria caused by 3NP. However, the detailed mechanism of cell death by 3NP and the protective actions of LC against the mitochondrial dysfunction have not been fully elucidated yet. Thus, we studied the molecular mechanism of the effects of 3NP and LC on isolated rat liver mitochondria. 3NP inhibited succinate respiration and the decreased respiratory control ratio of isolated mitochondria without affecting oxidative phosphorylation. 3NP induced a membrane permeability transition (MPT), which plays an important role in the mechanism of apoptotic cell death. 3NP stimulated Ca 2þ release from mitochondria, decreased membrane potential, induced mitochondrial swelling, and stimulated cytochrome c release from mitochondria. 3NP-induced swelling was suppressed by bovine serum albumin, inhibitors of phospholipase A 2 and by an inhibitor of classic MPT, cyclosporin A. Furthermore, LC suppressed the changes brought about by 3NP in mitochondrial functions in the presence of ATP. These results suggest that MPT underlies the mechanism of 3NP-induced cell death, and that LC attenuates mitochondrial MPT by decreasing long chain fatty acids generated by phospholipase A 2 .

Involvement of mGlu5 receptor in 3-nitropropionic acid-induced oxidative stress in rat striatum

“…44 Our results show that 3-NP inhibited Na z -K z ATPase activity, corroborating the hypothesis that Na z -K z ATPase dysfunction or deficiency is a common event in neurodegenerative diseases. 45 It is important to consider that 3-NP treatment modified mitochondrial enzyme complex activities (as evidenced by changes in SDH activity), which could generate free radicals and reduce ATP content in the rat striatum.…”

Brief mitochondrial inhibition causes lasting changes in motor behavior and corticostriatal synaptic physiology in the Fischer 344 rat

“…3-NP’s primary pharmacological effect is block of succinic acid dehydrogenase (complex II) (Huang et al, 2006; Nishimura et al, 2008). This direct pharmacological action leads to increased reactive oxygen species (ROS) production, reduced ATP production and the formation of mitochondrial permeability transition pores (Huang et al, 2006; Nishimura et al, 2008).…”

“…This direct pharmacological action leads to increased reactive oxygen species (ROS) production, reduced ATP production and the formation of mitochondrial permeability transition pores (Huang et al, 2006; Nishimura et al, 2008). One consequence of a drop in ATP production is reduced activity of Ca2 + pumps and the Na + /K + ATPase, which causes neurons to depolarize.…”

Autophagy as a Neuroprotective Mechanism Against 3-Nitropropionic Acid-Induced Cell Death

“…3-NP stimulates Ca 2 + release from mitochondria, decreases membrane potential, induces mitochondrial swelling and stimulates cytochrome c release from mitochondria [50][51][52][53][54].…”