Gatliff Jemma, East Daniel A, Singh Aarti, Alvarez Maria Soledad, Frison Michele, Matic Ivana, Ferraina Caterina, Sampson Natalie, Turkheimer Federico, Campanella Michelangelo
Department of Comparative Biomedical Sciences, The Royal Veterinary College, University of London, Royal College Street, London NW1 0TU, UK.
Regina Elena-National Cancer Institute, 00144 Rome, Italy.
Cell Death Dis. 2017 Jun 22;8(6):e2896. doi: 10.1038/cddis.2017.186.
The 18 kDa translocator protein TSPO localizes on the outer mitochondrial membrane (OMM). Systematically overexpressed at sites of neuroinflammation it is adopted as a biomarker of brain conditions. TSPO inhibits the autophagic removal of mitochondria by limiting PARK2-mediated mitochondrial ubiquitination via a peri-organelle accumulation of reactive oxygen species (ROS). Here we describe that TSPO deregulates mitochondrial Ca signaling leading to a parallel increase in the cytosolic Ca pools that activate the Ca-dependent NADPH oxidase (NOX) thereby increasing ROS. The inhibition of mitochondrial Ca uptake by TSPO is a consequence of the phosphorylation of the voltage-dependent anion channel (VDAC1) by the protein kinase A (PKA), which is recruited to the mitochondria, in complex with the Acyl-CoA binding domain containing 3 (ACBD3). Notably, the neurotransmitter glutamate, which contributes neuronal toxicity in age-dependent conditions, triggers this TSPO-dependent mechanism of cell signaling leading to cellular demise. TSPO is therefore proposed as a novel OMM-based pathway to control intracellular Ca dynamics and redox transients in neuronal cytotoxicity.
18千道尔顿转位蛋白TSPO定位于线粒体外膜（OMM）。它在神经炎症部位系统性过表达，被用作脑部疾病的生物标志物。TSPO通过限制活性氧（ROS）在细胞器周围的积累，抑制PARK2介导的线粒体泛素化，从而抑制线粒体的自噬清除。在此我们描述，TSPO会使线粒体钙信号失调，导致胞质钙池平行增加，进而激活钙依赖性NADPH氧化酶（NOX），从而增加ROS。TSPO对线粒体钙摄取的抑制作用是蛋白激酶A（PKA）对电压依赖性阴离子通道（VDAC1）进行磷酸化的结果，PKA与含酰基辅酶A结合域3（ACBD3）形成复合物后被募集到线粒体。值得注意的是，在年龄依赖性疾病中具有神经毒性作用的神经递质谷氨酸，会触发这种依赖TSPO的细胞信号传导机制，导致细胞死亡。因此，TSPO被认为是一种基于线粒体外膜的新途径，可控制神经元细胞毒性中的细胞内钙动力学和氧化还原瞬变。
