粒線體功能異常對人體神經細胞的影響(2/2)

Abstract

3-Nitropropionic acid (3-NP), an irreversible inhibitor of succinate dehydrogenase, induced ATP depletion and both necrosis and apoptosis in human NT2-N neurons. Necrosis occurred predominantly during the first 2 days in a dose-dependent manner, whereas apoptosis was observed after 24 hr or later at a low constant rate in 0.1mM as well as 5mM 3-NP. We assayed the intracellular concentration of Ca24- ([Ca2j1) during the first 48 hours in 1mM 3-NP, a period during which 10% of the neurons died by necrosis and 3% by apoptosis. During the first 2 hours in 3-NP, all NT2-N neurons showed [Ca2j1 rise from48¡Ó2 to 140¡Ó l2nM(mean¡ÓSEM¡¦). After 24 and 48 hours in 3-NP, however, [Ca24-J remained above IOOnM in only 17% and 25% of the NT2-N neurons, respectively, suggesting that most neurons were able to correct this early rise in [Ca24-], despite severe ATP depletion, and to survive. Activation of NMDA-GIuR contributed substantially to 3-NP-induced ATP depletion, and subsequent chronic elevation of [Ca24-]1 in the NT2-N neurons. We also demonstrated that blocking endoplasmic reticulum (ER) Ca24- release enhanced the capacity of these human neurons to maintain [Ca21], homeostasis and resist necrosis while subjected to chronic energy deprivation.