Bernardinelli Emanuele, Costa Roberta, Scantamburlo Giada, To Janet, Morabito Rossana, Nofziger Charity, Doerrier Carolina, Krumschnabel Gerhard, Paulmichl Markus, Dossena Silvia
Institute of Pharmacology and Toxicology, Paracelsus Medical University, Salzburg, Austria.
School of Biological Sciences, Nanyang Technological University, Singapore, Singapore.
PLoS One. 2017 Jun 19;12(6):e0179591. doi: 10.1371/journal.pone.0179591. eCollection 2017.
Lipoyl(Octanoyl) Transferase 2 (LIPT2) is a protein involved in the post-translational modification of key energy metabolism enzymes in humans. Defects of lipoic acid synthesis and transfer start to emerge as causes of fatal or severe early-onset disease. We show that the first 31 amino acids of the N-terminus of LIPT2 represent a mitochondrial targeting sequence and inhibition of the transit of LIPT2 to the mitochondrion results in apoptotic cell death associated with activation of the apoptotic volume decrease (AVD) current in normotonic conditions, as well as over-activation of the swelling-activated chloride current (IClswell), mitochondrial membrane potential collapse, caspase-3 cleavage and nuclear DNA fragmentation. The findings presented here may help elucidate the molecular mechanisms underlying derangements of lipoic acid biosynthesis.
脂酰（辛酰）转移酶2（LIPT2）是一种参与人类关键能量代谢酶翻译后修饰的蛋白质。硫辛酸合成和转移缺陷开始成为致命或严重早发性疾病的病因。我们发现，LIPT2 N端的前31个氨基酸代表一个线粒体靶向序列，抑制LIPT2向线粒体的转运会导致凋亡性细胞死亡，这与等渗条件下凋亡体积减小（AVD）电流的激活以及肿胀激活的氯离子电流（IClswell）的过度激活、线粒体膜电位崩溃、半胱天冬酶-3裂解和核DNA片段化有关。本文的研究结果可能有助于阐明硫辛酸生物合成紊乱的分子机制。
